Method for manufacturing neuraminic acid derivatives

ABSTRACT

A method of manufacturing a compound represented by the formula R 1 C(OR 7 ) 3 , wherein R 1  represents a C 1 -C 19  alkyl group and R 7  represents a C 1 -C 6  alkyl group by reacting a compound represented by the following formula (15): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 1  represents a C 1 -C 19  alkyl group, R 7  represents a C 1 -C 6  alkyl group and X represents Cl, Br, I, HSO 4  or NO 3 , with a compound represented by the formula R 7 —OH, wherein R 7  represents a C 1 -C 6  alkyl group, in a solvent which forms a bilayer system.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of application Ser. No.13/966,863 filed Aug. 14, 2013, which is a divisional application ofapplication Ser. No. 13/795,050 filed Mar. 12, 2013 (U.S. Pat. No.8,575,370), which is a divisional application of application Ser. No.12/450,699 filed Oct. 7, 2009 (U.S. Pat. No. 8,455,659), which is theUnited States national phase application under 35 USC 371 ofInternational application PCT/JP2008/057557 filed Apr. 11, 2008. Theentire contents of each of application Ser. No. 13/966,863, applicationSer. No. 13/795,050, application Ser. No. 12/450,699 and Internationalapplication PCT/JP2008/057557 are hereby incorporated by referenceherein.

TECHNICAL FIELD

The present invention relates to a method for manufacturing neuraminicacid derivatives which have neuraminidase inhibitory activity, and tosynthetic intermediates of the neuraminic acid derivatives and methodsfor their manufacture. In addition, the present invention relates toneuraminic acid derivatives having high purity.

A compound represented by the formula (I):

[wherein R₁ represents a C₁-C₁₉ alkyl group and R₂ represents aC₁-C₄alkyl group] or a pharmacologically acceptable salt thereof isknown to have excellent neuraminidase inhibitory activity and thereforeto be useful as a drug for treatment or prevention of influenza (PatentDocument 1 or 2).

A trifluoroacetic acid salt of a compound represented by the formula(III):

is known to have excellent neuraminidase inhibitory activity andtherefore to be useful as a drug for treatment or prevention ofinfluenza (Non-patent Document 1 or 2).

Process W is known as a method for manufacturing a compound representedby the formula (Ia), which is embraced in a compound represented by theformula (I) or a pharmacologically acceptable salt thereof, [hereinafteralso referred to as “compound (Ia)”; the same shall be applied withrespect to other formulas] (Patent Document 1). In Process W, n-Heprepresents a 1-heptyl group.

Process X is known as a method for manufacturing compound (Ib), which isembraced in compound (I) or a pharmacologically acceptable salt thereof(Patent Document 2). Compound (IVk) is a synthetic intermediate inProcess W. In Process X, n-Hep represents a 1-heptyl group.

Process Y is known as a method for manufacturing compound (IIIa), whichis a trifluoroacetic acid salt of compound (III) (Non-patent Document1). The procedures from compound (IVc) to compound (IVe) and fromcompound (IVf) to compound (IVh) in Process Y are the same as in ProcessW.

Process Z is known as a method for manufacturing compound (IIIa), whichis a trifluoroacetic acid salt of compound (III) (Non-patent Document2). In Process Z, the procedure from compound (IVf) to compound (IVh) isthe same as in Process W, and the procedure from compound (IVh) tocompound (IIIa) is the same as in Process Y.

From the viewpoint of industrial production, the aforementioned ProcessW, Process Y, or Process Z could be improved in points such as thefollowing:

[Process W]

(1) the overall yield is low since a procedure with a low yield isincluded [overall yield of compound (Ia): 0.2%];(2) N-methylation of an acetamide group occurs as a side reaction ofmethylation reaction of a hydroxy group [production procedure ofcompound (IVb)];(3) an inefficient enzyme reaction is included [production procedure ofcompound (IVd)];(4) a hazardous azidation reaction at high temperature is included[production procedure of compound (IVg)]; or(5) in the acylation reaction, (a) protection of a carboxyl group isnecessary, (b) 2,3-diacylated product is generated as by-product, and(c) purification by silica gel column chromatography is necessary toremove octanoic acid derived from the reagent [production procedure ofcompound (IVk)];

[Process Y]

(1) the overall yield is low since a procedure with a low yield isincluded [yield of compound (Va): 34%, overall yield from compound (Va)to compound (IIIa): 10 to 23%, resulting in 3 to 8%];(2) an inefficient enzyme reaction is included [production procedure ofcompound (IVd)]; or(3) a hazardous azidation reaction at high temperature is included[production procedure of compound (IVg)];

[Process Z]

(1) the overall yield is low since a procedure with a low yield isincluded [yield of compound (VIa): 35%, overall yield from compound(VIa) to compound (IIIa): 1 to 33%, resulting in 0.4 to 12%];(2) an expensive silyl protective group is used;(3) N-methylation of an acetamide group occurs as a side reaction of themethylation reaction of a hydroxy group [production procedure ofcompound (IVb)]; or(4) a hazardous azidation reaction at high temperature is included[production procedure of compound (IVg)].

-   [Patent Document 1] U.S. Pat. No. 6,340,702 (corresponding to    Japanese Patent No. 3209946)-   [Patent Document 2] U.S. Pat. No. 6,844,363 (corresponding to    Japanese Patent Application No. 2002-012590)-   [Non-patent Document 1] T. Honda et al., Bioorganic Medicinal    Chemistry Letters, 2002, pp. 1921-1924-   [Non-patent Document 2] T. Honda et al., Bioorganic Medicinal    Chemistry Letters, 2002, pp. 1925-1928

As a result of conducting extensive studies on methods for manufacturingneuraminic acid derivatives, the inventors of the present invention havefound a novel method for manufacturing neuraminic acid derivatives vianovel synthetic intermediates of the present invention that is superiorto publicly known manufacturing methods from an industrial perspective,and have found that neuraminic acid derivatives with high purity can beobtained in high yield by the manufacturing method. The presentinvention has been completed based on the aforementioned findings.

SUMMARY OF THE INVENTION

The present invention provides a method for manufacturing neuraminicacid derivatives which have neuraminidase inhibitory activity, andsynthetic intermediates of the neuraminic acid derivatives and methodsfor their manufacture. In addition, the present invention providesneuraminic acid derivatives having high purity.

The present invention provides a method for manufacturing a neuraminicacid derivative shown by the following Process A:

In the aforementioned Process A, R¹ represents a C₁-C₁₉ alkyl group, R²represents a C₁-C₄ alkyl group, R³, R⁶ and R⁷, independently from oneanother, represent a C₁-C₆ alkyl group, R⁴ and R⁵, independently fromeach other, represent a hydrogen atom, a C₁-C₆ alkyl group or a phenylgroup, or R⁴ and R⁵ together form a tetramethylene group, apentamethylene group or oxo group except that R⁴ and R⁵ in compound (6)do not form an oxo group. Here, Ac represents an acetyl group, Bocrepresents a tert-butoxycarbonyl group, and Ph represents a phenylgroup. The same applies for these three groups hereinafter.

According to one aspect of the present invention, there is provided

[1] a method for manufacturing a compound represented by the formula (7)

[wherein R³ represents a C₁-C₆ alkyl group, and R⁴ and R⁵, independentlyfrom each other, represent a hydrogen atom, a C₁-C₆ alkyl group or aphenyl group, or R⁴ and R⁵ together form a tetramethylene group, apentamethylene group or an oxo group], comprising:allowing a compound represented by the formula (4):

[wherein R³ represents a C₁-C₆ alkyl group] to react with a compoundrepresented by the formula (5):

[wherein R⁴ and R⁵, independently from each other, represent a hydrogenatom, a C₁-C₆ alkyl group or a phenyl group, or R⁴ and R⁵ together forma tetramethylene group, a pentamethylene group or an oxo group, and R⁶represents a C₁-C₆ alkyl group], or with a compound represented by theformula (6):

[wherein R⁴ and R⁵, independently from each other, represent a hydrogenatom, a C₁-C₆ alkyl group or a phenyl group, or R⁴ and R⁵ together forma tetramethylene group or a pentamethylene group] except that R⁴ and R⁵in compound (7) do not together form an oxo group when compound (6) isused,[2] the manufacturing method as described in [1], wherein a compoundrepresented by the formula (7) is manufactured by the reaction of acompound represented by the formula (4) with a compound represented bythe formula (5), andR³ is a methyl group, R⁴ and R⁵ together form an oxo group, and thecompound represented by the formula (5) is dimethyl carbonate,[3] a compound represented by the formula (7):

[wherein R³ represents a C₁-C₆ alkyl group, R⁴ and R⁵, independentlyfrom each other, represent a hydrogen atom, a C₁-C₆ alkyl group or aphenyl group, or R⁴ and R⁵ together form a tetramethylene group, apentamethylene group or an oxo group],[4] the compound as described in [3], wherein R³ is a methyl group, andR⁴ and R⁵ together form an oxo group,[5] a method for manufacturing a compound represented by the formula (9)

[wherein R² represents a C₁-C₄ alkyl group, R³ represents a C₁-C₆ alkylgroup, and R⁴ and R⁵, independently from each other, represent ahydrogen atom, a C₁-C₆ alkyl group or a phenyl group, or R⁴ and R⁵together form a tetramethylene group, a pentamethylene group or an oxogroup], comprising: allowing a compound represented by the formula (8):

[wherein R² represents a C₁-C₄ alkyl group, R³ represents a C₁-C₆ alkylgroup, R⁴ and R⁵, independently from each other, represent a hydrogenatom, a C₁-C₆ alkyl group or a phenyl group, or R⁴ and R⁵ together forma tetramethylene group, a pentamethylene group or an oxo group] to reactwith trimethylsilyl azide in the presence of a Lewis acid,[6] the manufacturing method as described in [5], wherein R² is a methylgroup, R³ is a methyl group, R⁴ and R⁵ together form an oxo group, andthe Lewis acid is titanium (IV) isopropoxide,[7] a method for manufacturing a compound represented by the formula(13):

[wherein R² represents a C₁-C₄ alkyl group], comprising: allowing acompound represented by the formula (12):

[wherein R² represents a C₁-C₄ alkyl group] to react with water,[8] the manufacturing method as described in [7], wherein R² is a methylgroup,[9] a compound represented by the formula (13):

[wherein R² represents a C₁-C₄ alkyl group],[10] the compound as described in [9], wherein R² is a methyl group,[11] a method for manufacturing a compound represented by the formula(I):

[wherein R¹ represents a C₁-C₁₉ alkyl group and R² represents a C₁-C₄alkyl group], [here, the compound represented by the formula (I) mayinclude a compound represented by the formula (II):

[wherein R¹ and R² have the same meanings as in the formula (I)]], or apharmacologically acceptable salt thereof comprising:allowing a compound represented by the formula (13):

[wherein R² represents a C₁-C₄ alkyl group] to react with a compoundrepresented by the formula R¹C(OR⁷)₃ [wherein R¹ represents a C₁-C₁₉alkyl group and R⁷ represents a C₁-C₆ alkyl group], or apharmacologically acceptable salt thereof,[12] the manufacturing method as described in [11], wherein R₁ is a1-heptyl group, R² is a methyl group, and R⁷ is a methyl group,[13] a method for manufacturing a compound represented by the formula(I):

[wherein R¹ represents a C₁-C₁₉ alkyl group and R² represents a C₁-C₄alkyl group], [here, the compound represented by the formula (I) mayinclude a compound represented by the formula (II):

[wherein R¹ and R² have the same meanings as in the formula (I)]] orpharmacologically acceptable salt thereof, comprising: allowing acompound represented by the formula (13):

[wherein R² represents a C₁-C₄ alkyl group] to react with a compoundrepresented by the formula (15):

[wherein R¹ represents a C₃-C₁₉ alkyl group, R⁷ represents a C₁-C₆ alkylgroup, and X represents Cl, Br, I, HSO₄ or NO₃], and with a compoundrepresented by the formula R⁷—OH [wherein R⁷ represents a C₁-C₆ alkylgroup],[14] the manufacturing method as described in [13], wherein R¹ is a1-heptyl group, R² is a methyl group, R⁷ is a methyl group, and X is Cl,[15] a method for manufacturing a compound represented by the formula(Ib):

[wherein Me represents a methyl group (the same applies hereinafter),and the compound represented by the formula (Ib) may include a compoundrepresented by the formula (IIb):

or a pharmacologically acceptable salt thereof, which includes at leastone manufacturing method described in any one of [2], [6] and [8] aspart of the production procedure,[16] a method for manufacturing a compound represented by the formula(Ib):

[wherein the compound represented by the formula (Ib) may include acompound represented by the formula (IIb):

or a pharmacologically acceptable salt thereof, which proceeds via atleast one compound described in either one of [4] and [10],[17] a compound represented by the formula (I):

[wherein R¹ represents a C₁-C₁₉ alkyl group and R² represents a C₁-C₄alkyl group], [here, the compound represented by the formula (I) mayinclude a compound represented by the formula (II):

[wherein R¹ and R² have the same meanings as in the formula (I)]] havinga chemical purity of 97 wt % or higher, [wherein in the case where thecompound represented by the formula (II) is included, the chemicalpurity of the mixture of the compound represented by the formula (I) andthe compound represented by the formula (II) is 97 wt % or higher], or apharmacologically acceptable salt thereof,[18] the compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [17], wherein the chemicalpurity is 99 wt % or higher,[19] the compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [17], wherein the chemicalpurity is 99.5 wt % or higher,[20] the compound represented by the formula (I), which may include thecompound represented by the formula (II), as described in any one of[17] through [19], wherein R¹ is a 1-heptyl group and R² is a methylgroup,[21] a compound represented by the formula (I):

[wherein R¹ represents a C₁-C₁₉ alkyl group and R² represents a C₁-C₄alkyl group], [here, the compound represented by the formula (I) mayinclude a compound represented by the formula (II):

[wherein R¹ and R² have the same meanings as in the formula (I)]], or apharmacologically acceptable salt thereof, containing a compoundrepresented by the formula (VII):

[wherein R¹ and R² represent have the same meanings as in the formula(I)] in an amount of 0.5 wt % or less,[22] a compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [21], containing the compoundrepresented by the formula (VII) in an amount of 0.3 wt % or less,[23] a compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [21], containing the compoundrepresented by the formula (VII) in an amount of 0.1% or less,[24] a compound represented by the formula (I), which may include thecompound represented by the formula (II), as described in any one of[21] through [23], wherein R¹ is a 1-heptyl group and R² is a methylgroup,[25] a compound represented by the formula (I):

[wherein R¹ represents a C₁-C₁₉ alkyl group and R² represents a C₁-C₄alkyl group], [here, the compound represented by the formula (I) mayinclude a compound represented by the formula (II):

[wherein R¹ and R² have the same meanings as in the formula (I)]], or apharmacologically acceptable salt thereof, containing a compoundrepresented by the formula (VIII):

[wherein R¹ has the same meaning as the formula (I)] in an amount of 0.5wt % or less,[26] a compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [25], containing the compoundrepresented by the formula (VIII) in amount of 0.3 wt % or less,[27] a compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptablesalt thereof as described in [25], containing the compound representedby the formula (VIII) in an amount of 0.1 wt % or less,[28] a compound represented by the formula (I), which may include thecompound represented by the formula (II) as described in any one of [25]through [27], wherein R¹ is a 1-heptyl group and R² is a methyl group,[29] a compound represented by the formula (I):

[wherein R¹ represents a C₁-C₁₉ alkyl group and R² represents a C₁-C₄alkyl group], [here, the compound represented by the formula (I) mayinclude a compound represented by the formula (II):

[wherein R¹ and R² have the same meanings as in the formula (I)]], or apharmacologically acceptable salt thereof, containing a compoundrepresented by the formula (13):

[wherein R² has the same meaning as in the formula (I)] in an amount of0.5 wt % or less,[30] a compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [29], containing the compoundrepresented by the formula (13) in an amount of 0.3 wt % or less,[31] a compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [29], containing the compoundrepresented by the formula (13) in an amount of 0.1 wt % or less,[32] a compound represented by the formula (I), which may include thecompound represented by the formula (II) as described in any one of [29]through [31], wherein R¹ is a 1-heptyl group and R² is a methyl group,[33] a compound represented by the formula (I), which may include acompound represented by the formula (II), as described in any one of[17] through [32], wherein the composition ratio of the compoundrepresented by the formula (I) and the compound represented by theformula (II) is 90:10 to 100:0 by weight,[34] a compound represented by the formula (I), which may include acompound represented by the formula (II), as described in any one of[17] through [32], wherein the composition ratio of the compoundrepresented by the formula (I) and the compound represented by theformula (II) is 92:8 to 100:0 by weight,[35] a compound represented by the formula (I), which may include acompound represented by the formula (II), as described in any one of[17] through [32], wherein the composition ratio of the compoundrepresented by the formula (I) and the compound represented by theformula (II) is 95:5 to 100:0 by weight,[36] a method for manufacturing a compound represented by the formulaR¹C(OR⁷)₃[wherein R¹ represents a C₁-C₁₉ alkyl group and R⁷ represents a C₂-C₆alkyl group], comprising:allowing a compound represented by the formula (15):

[wherein R¹ represents a C₁-C₁₉ alkyl group, R⁷ represents a C₁-C₆ alkylgroup, and X represents Cl, Br, I, HSO₄ or NO₃] to react with a compoundrepresented by the formula R⁷—OH [wherein R⁷ represents a C₁-C₆ alkylgroup] in a solvent which forms a bilayer system,[37] the manufacturing method as described in [36], wherein the solventwhich forms the bilayer system is a hydrocarbon,[38] the manufacturing method as described in [36], wherein the solventwhich forms the bilayer system is cyclohexane or methylcyclohexane,[39] the manufacturing method as described in any one of [36] through[38], wherein R¹ is a 1-heptyl group, R⁷ is a methyl group, and X is Cl,[40] a composition for treatment or prevention of influenza containingas active ingredient the compound or pharmacologically acceptable saltsthereof as set forth in any one of [17] through [35],[41] a compound represented by the formula (I):

[wherein R¹ represents a C₁-C₁₉ alkyl group and R² represents a C₁-C₄alkyl group], [here, the compound represented by the formula (I) mayinclude a compound represented by the formula (II):

[wherein R¹ and R² have the same meanings as in the formula (I)]] havinga chemical purity of 97 wt % or higher, [wherein in the case where thecompound represented by the formula (II) is included, the chemicalpurity of the mixture of the compound represented by the formula (I) andthe compound represented by the formula (II) is 97 wt % or higher], or apharmacologically acceptable salt thereof, manufactured by a methodcomprising: allowing a compound represented by the formula (13):

[wherein R² represents a C₁-C₄ alkyl group] to react with a compoundrepresented by the formula R¹C(OR⁷).₃ [wherein R¹ represents a C₁-C₁₉alkyl group and R⁷ represents a C₁-C₆ alkyl group], or apharmacologically acceptable salt thereof,[42] the compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [41], wherein the chemicalpurity is 99 wt % or higher,[43] the compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [41], wherein the chemicalpurity is 99.5 wt % or higher,[44] the compound represented by the formula (I), which may include thecompound represented by the formula (II), as described in any one of[41] through [43], wherein R¹ is a 1-heptyl group and R² is a methylgroup,[45] a compound represented by the formula (I):

[wherein R¹ represents a C₁-C₁₉ alkyl group and R² represents a C₁-C₄alkyl group], [here, the compound represented by the formula (I) mayinclude a compound represented by the formula (II):

[wherein R¹ and R² have the same meanings as in the formula (I)]], or apharmacologically acceptable salt thereof, containing a compoundrepresented by the formula (VII):

[wherein R¹ and R² represent have the same meanings as in the formula(I)] in an amount of 0.5 wt % or less, manufactured by a methodcomprising:allowing a compound represented by the formula (13):

[wherein R² represents a C₁-C₄ alkyl group] to react with a compoundrepresented by the formula R¹C(OR⁷)₃ [wherein R¹ represents a C₁-C₁₉alkyl group and R⁷ represents a C₁-C₆ alkyl group],[46] the compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [45], containing the compoundrepresented by the formula (VII) in an amount of 0.3 wt % or less,[47] the compound represented by the formula (I), which may include thecompound represented by the formula (II), or a pharmacologicallyacceptable salt thereof as described in [45], containing the compoundrepresented by the formula (VII) in an amount of 0.1 wt % or less,[48] the compound represented by the formula (I), which may include thecompound represented by the formula (II), as described in any one of[45] through [47], wherein R¹ is a 1-heptyl group and R² is a methylgroup,[49] a compound represented by the formula (I):

[wherein R¹ represents a C₁-C₁₉ alkyl group and R² represents a C₁-C₄alkyl group], [here, the compound represented by the formula (I) mayinclude a compound represented by the formula (II):

[wherein R¹ and R² have the same meanings as in the formula (I)]], or apharmacologically acceptable salt thereof, containing a compoundrepresented by the formula (VIII):

[wherein R¹ has the same meaning as in the formula (I)] in an amount of0.5 wt % or less, manufactured by a method comprising:allowing a compound represented by the formula (13):

[wherein R² represents a C₁-C₄ alkyl group] to react with a compoundrepresented by the formula R¹C(OR⁷)₃ [wherein R¹ represents a C₁-C₁₉alkyl group and R⁷ represents a C₁-C₆ alkyl group],[50] the compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [49], containing the compoundrepresented by the formula (VIII) in an amount of 0.3 wt % or less,[51] the compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [49], containing the compoundrepresented by the formula (VIII) in an amount of 0.1 wt % or less,[52] the compound represented by the formula (I), which may include thecompound represented by the formula (II) as described in any one of [49]through [51], wherein R¹ is a 1-heptyl group and R² is a methyl group,[53] a compound represented by the formula (I):

[wherein R¹ represents a C₁-C₁₉ alkyl group and R² represents a. C₁-C₄alkyl group], [here, the compound represented by the formula (I) mayinclude a compound represented by the formula (II):

[wherein R¹ and R² have the same meanings as in the formula (I)]], or apharmacologically acceptable salt thereof, containing an unconvertedmaterial compound represented by the formula (13):

[wherein R² has the same meaning as in the formula (I)] in an amount of0.5 wt % or less, manufactured by a method comprising:allowing a compound represented by the formula (13):

[wherein R² represents a C₂-C₄ alkyl group] to react with a compoundrepresented by the formula R¹C(OR⁷)₃ [wherein R¹ represents a C₁-C₁₉alkyl group and R⁷ represents a C₁-C₆ alkyl group],[54] the compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [53], containing the compoundrepresented by the formula (13) in an amount of 0.3 wt % or less,[55] the compound represented by the formula (I), which may include thecompound represented by the formula (II), or pharmacologicallyacceptable salt thereof as described in [53], containing the compoundrepresented by the formula (13) in an amount of 0.1 wt % or less, or[56] the compound represented by the formula (I), which may include thecompound represented by the formula (II) as described in any one of [53]through [55], wherein R¹ is a 1-heptyl group and R² is a methyl group.

In the present invention, “C₁-C₁₉ alkyl group” of R¹ represents a linearor branched alkyl group having 1 to 19 carbon atoms, and may be forexample, a methyl group, ethyl group, propyl group, butyl group, pentylgroup, hexyl group, heptyl group, octyl group, nonyl group, decanylgroup, undecanyl group, dodecanyl group, tridecanyl group, tetradecanylgroup, pentadecanyl group, hexadecanyl group, heptadecanyl group,octadecanyl group or nonadecanyl group, preferably a C₅-C₁₉ alkyl group,more preferably a C₅-C₁₇ alkyl group, even more preferably a pentylgroup, heptyl group, nonyl group, undecanyl group, tridecanyl group,pentadecanyl group or heptadecanyl group, further preferably a 1-pentylgroup, 1-heptyl group, 1-nonyl group, 1-undecanyl group, 1-tridecanylgroup, 1-pentadecanyl group or 1-heptadecanyl group, and most preferablya 1-heptyl group.

“C₁-C₄ alkyl group” of R² represents a linear or branched alkyl grouphaving 1 to 4 carbon atoms, and may be for example, a methyl group,ethyl group, propyl group or butyl group, preferably a methyl group orethyl group, and most preferably a methyl group.

“C₁-C₆ alkyl group” in R³, R⁴, R⁵, R⁶ and R⁷ is a linear or branchedalkyl group having 1 to 6 carbon atoms, and may be for example, a methylgroup, ethyl group, propyl group, butyl group, pentyl group or hexylgroup, preferably a C₁-C₄ alkyl group, more preferably a methyl group orethyl group, and most preferably a methyl group.

R⁴ and R⁵ are preferably a hydrogen atom or a C₁-C₄ alkyl group, morepreferably a methyl group or ethyl group, and most preferably a methylgroup. R⁴ and R⁵ are preferably the same. Further, R⁴ and R⁵ preferablytogether form an oxo group.

In the present invention, “pharmacologically acceptable salt” may be,for example, a hydrohalic acid salt such as hydrofluoric acid salt,hydrochloric acid salt, hydrobromic acid salt and hydroiodic acid salt;an inorganic acid salt such as nitric acid salt, perchloric acid salt,sulfuric acid salt and phosphoric acid salt; an alkanesulfonic acid saltsuch as methanesulfonic acid salt, ethanesulfonic acid salt andtrifluoromethanesulfonic acid salt; an arylsulfonic acid salt such asbenzenesulfonic acid salt and p-toluenesulfonic acid salt; an organicacid salt such as acetic acid salt, trifluoroacetic acid salt, citricacid salt, tartaric acid salt, oxalic acid salt and maleic acid salt; anamino acid salt such as glycine salt, lysine salt, arginine salt,ornitine salt, glutamic acid salt and aspartic acid salt; an alkalimetal salt such as lithium salt, sodium salt and potassium salt; analkaline earth metal salt such as calcium salt and magnesium salt; ametal salt such as aluminum salt, iron salt, zinc salt, copper salt,nickel salt and cobalt salt; or an organic amine salt or organicammonium salt such as ammonium salt, t-octylamine salt, dibenzylaminesalt, morpholine salt, glucosamine salt, ethylenediamine salt, guanidinesalt, diethylamine salt, triethylamine salt, dicyclohexylamine salt,procain salt, ethanolamine salt, diethanolamine salt, piperazine saltand tetramethylammonium salt, preferably a hydrohalic acid salt ororganic acid salt, and more preferably trifluoroacetic acid salt.

When the compounds of the present invention are exposed to theatmosphere or are blended with water or organic solvent, they may formhydrates or solvates. Such hydrates and solvates are also embraced inthe compounds of the present invention. Compound (Ib) and compound (IIb)include an anhydride and hydrates. Preferably, the hydrate of compound(Ib) and hydrate of compound (IIb) are monohydrates.

The compounds of the present invention have an asymmetric carbon atomwithin their molecule, and thus there exist stereoisomers (enantiomersand diastereomers are included). These stereoisomers and mixturesthereof in an arbitrary ratio (including racemic form) are embraced inthe compounds of the present invention.

It is known that when compound (I) is administered to a warm-bloodedanimal, the acyloxy group at the 3-position of the side chain isconverted into a hydroxyl group by a metabolic reaction such ashydrolysis, and the generated compound (III) shows pharmacologicalactivity (Patent Document 1 and the like). In addition, when compound(II) is administered to a warm-blooded animal, the acyloxy group at the2-position of the side chain is converted into a hydroxyl group by ametabolic reaction such as hydrolysis, and compound (III) is generatedin a similar manner. Since both compound (I) and compound (II) areconverted into the same compound (III), which is an active metabolite,within an organism of a warm-blooded animal, it can be considered thatboth the compounds are active ingredients, from the point of view ofusing a mixture of compound (I) and compound (II) as a medicament. Onthe other hand, since a medicament is required to show a constantpharmacological effect and physical and chemical stability, it ispreferable that the composition ratio of these compounds is constant,from the point of view of the quality of a mixture of compound (I) andcompound (II) as a medicament.

In the present invention, the chemical purity of the compound, thecontent of a compound as an impurity, or the composition ratio of amixture of compound (I) and compound (II) may be determined by methodsknown in the field of organic chemistry (for example, high performanceliquid chromatography, weight %, and the like), and is preferablydetermined by peak area ratios under high performance liquidchromatography (hereinafter also referred to as HPLC). The measurementconditions for HPLC shall be selected appropriately; however, they arepreferably as shown hereinbelow.

HPLC Measurement Conditions (1)

Column: L-column ODS (4.6 mmID×25 cm, particle diameter 5 μm,manufactured by Chemicals Evaluation and Research Institute)Column temperature: 30° C.Measurement wavelength: 210 nmMobile phase:

A: 0.1% PIC B-7 (Low UV, manufactured by Waters Corporation) aqueoussolution/acetonitrile (9/1, v/v)

B: 0.1 mol/l phosphate buffer solution (pH 3.0)/acetonitrile (7/3, v/v)

[Here, 0.1 mol/l phosphate buffer solution (pH 3.0) is a buffer solutionprepared by adding 0.1 mol/l phosphoric acid to 0.1 mol/l aqueouspotassium dihydrogen phosphate solution to adjust its pH to 3.0.]

Gradient Conditions:

Time (min.) Mobile phase A (%) Mobile phase B (%) 0-3 100  0  3-23 100→00→100 23-90  0 100Flow rate: 1 ml/minSample concentration: approximately 1 g/lInjection amount: 20 μlRange detected with peak: from 0 minute to approximately 1.2 times thelength of retention time of compound (I)

HPLC Measurement Conditions (2)

Column: L-column ODS (4.6 mmID×25 cm, particle diameter 5 μm,manufactured by Chemicals Evaluation and Research Institute)Column temperature: 30° C.Measurement wavelength: 210 nmMobile phase:

0.1 mol/l phosphate buffer solution (pH 3.0)/acetonitrile (23/17, v/v)

[Here, 0.1 mol/l phosphate buffer solution (pH 3.0) is a buffer solutionprepared by adding 0.1 mol/l phosphoric acid to 0.1 mol/l aqueouspotassium dihydrogen phosphate solution to adjust its pH to 3.0.]Flow rate: 1 ml/minSample concentration: approximately 1 g/lInjection amount: 20 μlRange detected with peak: from approximately 1.2 times to 18 times thelength of retention time of compound (I)

By HPLC measurement conditions (1), the peak area ratios of compound(I), compound (II), and compound as impurity, which are detected from 0minute to approximately 1.2 times the length of retention time ofcompound (I), are measured. By HPLC measurement conditions (2), the peakarea ratio of compound as impurity, which is detected from approximately1.2 times to 18 times of the length of retention time of compound (I),is measured. Here, the peaks of the compounds as impurities representthe peaks when the peak of compound (I), the peak of compound (II), andthe peaks detected when solvent alone is injected [for example, the peakof solvent and the peak derived from noise], are subtracted from all ofthe peaks that are detected as 0.01% or more.

The chemical purity (%) of compound (I) can be calculated according tothe following equation.

Chemical purity of compound (I)−100−sum of peak area ratio (%) ofcompound as impurity

Compound (I) may include compound (II), and in the case where compound(I) includes compound (II), the chemical purity is calculated as themixture of compound (I) and compound (II).

The content of compound (VII) can be calculated as the peak area ratiounder HPLC measurement conditions (2). The content of compound (VIII)and compound (13) can be calculated as the peak area ratio under HPLCmeasurement conditions (1).

The peak area ratios of compound (I) and compound (II) can be measuredin accordance with the aforementioned HPLC measurement conditions (1).The composition ratio (%) of a mixture of compound (I) and compound (II)can be calculated from the following equation.

Composition ratio of compound (I)=[peak area ratio of compound (I)/[peakarea ratio of compound (I)+peak area ratio of compound (II)]]×100

Composition ratio of compound (II)=[peak area ratio of compound(II)/[peak area ratio of compound (I)+peak area ratio of compound(II)]]×100

The chemical purity of compound (I) or pharmacologically acceptable saltthereof is preferably 95% or more, more preferably 97% or more, evenmore preferably 98% or more, further preferably 99% or more, and mostpreferably 99.5% or more, by weight. Compound (I) may contain compound(II), and in the case where compound (I) contains compounds (II), thechemical purity is calculated by taking both compound (I) and compound(II) as active ingredients. It is more preferable that the content ofcompounds other than compound (I) [and compound (II)] orpharmacologically acceptable salt thereof is below the detection limit.

Concerning compound (I) which may contain compound (II), the compositionratio of compound (I) and compound (II) is preferably 85:15 to 100:0,more preferably 90:10 to 100:0, even more preferably 92:8 to 100:0, andmost preferably 95:5 to 100:0, by weight. The content of a compoundrepresented by formula (II) may be below the detection limit.

Concerning compound (I) or pharmacologically acceptable salt thereof,the content of compound (VII) is preferably 2% or less, more preferably1% or less, even more preferably 0.5% or less, further preferably 0.3%or less, and most preferably 0.1% or less, by weight. It is morepreferable that the content of compound (VII) is below the detectionlimit.

Concerning compound (I) or pharmacologically acceptable salt thereof,the content of compound (VIII) is preferably 2% or less, more preferably1% or less, even more preferably 0.5% or less, further preferably 0.3%or less, and most preferably 0.1% or less, by weight. It is morepreferable that the content of compound (VIII) is below the detectionlimit.

Concerning compound (I) or pharmacologically acceptable salt thereof,the content of compound (13) is preferably 2% or less, more preferably1% or less, even more preferably 0.5% or less, further preferably 0.3%or less, and most preferably 0.1% or less, by weight. It is morepreferable that the content of compound (13) is below the detectionlimit.

The present invention shown by Process A is superior to publicly knownmanufacturing methods or synthetic intermediates, in points given below,for example.

(i) Concerning the production procedures of compound (IVb) of Process Wand compound (VIb) of Process Z, since an acetamide group exists intheir starting materials compound (IVa) and compound (VIa),N-methylation occurs as a side reaction. For example, with respect tocompound (VIa), the N-methylated compound is generated at approximately12% (refer to data of N-methylated compound of compound (VIa) describedin Comparative Example 1).

In contrast, compound (7) has no functional group which may bemethylated other than the hydroxyl group at the 1-position of the sidechain, and thus N-methylation as a side reaction does not occur in themethylation reaction of compound (7). In addition, the oxazolidine ringof compound (7) simultaneously serves as a protective group to preventN-methylation and as a partial structure which is to be converted intoan acetamide group at the 5-position in Step A-6. Further, sincecompound (7) is a crystalline solid, it can easily be purified byrecrystallization. Therefore, compound (7) contributes to theimprovement of the overall yield in Process A, by achieving efficientmethylation of the hydroxyl group at the 1-position of the side chain,and by achieving a reduction in the number of procedures in Process A.

(ii) Concerning the production procedure of compound (IVg) in Process W,Process Y, and Process Z, since the reaction is carried out under a hightemperature of 80° C. or higher using approximately 6 moles of sodiumazide, it is extremely hazardous especially from an industrialperspective, when the explosive nature of azide compounds is taken intoconsideration. In addition, the stereoselectivity of the reaction at the4-position is not enough, and thus the generation ratio of compound(IVg) and the undesired stereoisomer in which the azide group has theopposite configuration of compound (IVg), is approximately 7:1 (refer toComparative Example 2).

In contrast, concerning the azidation reaction of compound (8), by usinga Lewis acid, the amount of azidation agent used is reduced toapproximately 1.5 to 2 equivalents, and the reaction proceeds underextremely mild conditions of 0° C. to 30° C. In addition, thestereoselectivity of the reaction at the 4-position is improved, andthus the generation ratio of compound (9) and the undesired stereoisomeris improved to 15:1 (refer to data described in Step A-6 of Example 1).

Accordingly, the manufacturing method of compound (9) from compound (8)improves the practicality of Process A from an industrial perspective,by achieving an improvement in the safety of the azidation reaction andstereoselective production of the desired isomer.

(iii) Compound (IIIa) in Process Y and Process Z is a salt oftrifluoroacetic acid which is corrosive, and is an amorphous solid,therefore being unable to be easily purified by recrystallization.

In contrast, compound (13) is produced from compound (12), by a reactionwith only water under mild conditions. In addition, since compound (13)is a crystalline solid, it can easily be purified by recrystallization.From an industrial perspective, it is extremely important to use astarting material with a purity as high as possible in the finalprocedure of the production, in order to obtain the desired compoundwith high purity. Therefore, compound (13) contributes to the productionof compound (I) with high purity, by providing a starting material withhigh purity in the final procedure.

(iv) Concerning the production procedure of compound (IVk) and compound(Ia) in Process W, (a) protection of a carboxyl group is necessary, (b)a 2,3-diacylated compound is generated as by-product, and (c)purification by silica gel column chromatography is required to removethe octanoic acid derived from the reagent. Here, as an acylationreaction of a hydroxyl group using an ortho ester, the followingreaction is known (Carbohydrate Research, 1987, Vol. 167, pp. 77-86).R^(a) represents a C₁-C₄ alkyl group and the like. In the followingreaction, the reactive functional group is a hydroxyl group only.

In contrast, no similar acylation reaction that proceeds in the presenceof a nitrogen functional group (guanidyl group), which is considered tobe more reactive, is known. In the production procedure of compound (I)from compound (13), an acylation reaction proceeds with a fine yield inthe presence of a guanidyl group. In the present procedure, (a′)protection of a carboxyl group is unnecessary, (b′) selectivemono-acylation proceeds, resulting in scarce generation of a2,3-diacylated compound as a by-product and (c′) removal of by-productderived from the reagent by silica gel column chromatography is notrequired. Therefore, the manufacturing method of compound (I) fromcompound (13) contributes largely to the production of compound (I) withhigh purity.

(v) An acylation reaction of a hydroxyl group using an imino ester isnot known to present date. The production procedure of compound (I) fromcompound (13) can also be conducted by using an imino ester compound(15) and a compound represented by the formula R⁷—OH, in place of anortho ester compound (14). The production of compound (14) by aconventional method is very low in yield [refer to (vii) given below].By using compound (15) directly, the inefficient production procedure ofcompound (14) from compound (15) can be omitted.

(vi) Concerning the production procedure of compound (IVk) and compound(Ia) in Process W, compound (VII), which is a 2,3-diacylated compound,is generated as a by-product. Accordingly, a reduction in the amount ofcompound (VII) contained is required to obtain compound (Ia) with highpurity (refer to Comparative Example 3).

In the production procedure of compound (I) from compound (13),selective monoacylation reaction can be achieved by using compound (14)or compound (15), and thus compound (I) in which the amount of compound(VII) contained is less to such an extent as to be practical, can beproduced (refer to Step A-10 of Example 1).

Therefore, the manufacturing method of compound (I) from compound (13)contributes largely to the production of compound (I) with high purity.

(vii) In the production of compound (14), when a compound represented bythe formula R⁷—OH is used as a reagent and as a solvent to react withcompound (15), following a publicly known method (Journal of AmericanChemical Society, 1942, vol. 64, pp. 1825-1827), the yield of compound(14) is approximately 35% to 50% (refer to Comparative Example 4).

In contrast, when compound (15) is allowed to react with a compoundrepresented by the formula R⁷—OH in a solvent which forms a bilayersystem, the yield of compound (14) is improved remarkably toapproximately 80% to 85% (refer to Example 9). Therefore, themanufacturing method of compound (14) from compound (15) contributes tothe improvement of the overall yield of Process A, by providing anefficient method of manufacturing compound (14), which is used in theproduction of compound (I).

Effect of the Invention

The novel method of manufacturing neuraminic acid derivatives via thenovel synthetic intermediate according to the present invention issuperior from an industrial perspective, compared with publicly knownmanufacturing methodes. In addition, neuraminic acid derivatives withhigh purity can be obtained in high yield by the present manufacturingmethod.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the present invention, the method of manufacturing neuraminic acidderivatives can be conducted in accordance with the following Process Athrough Process G.

In Process A through Process G, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and X havethe same meanings as described above.

The solvent used in the reactions of each of the steps of Process Athrough Process G is not limited so long as it does not inhibit thereaction and dissolves the starting material to some degree, and can be,for example, selected from the following solvent group. The solventgroup comprises aliphatic hydrocarbons such as hexane, pentane,petroleum ether and cyclohexane; aromatic hydrocarbons such as benzene,toluene and xylene; halogenated hydrocarbons such as methylene chloride,chloroform, carbon tetrachloride, dichloroethane, chlorobenzene anddichlorobenzene; ethers such as diethyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethoxyethane and diethyleneglycol dimethylether; ketones such as acetone, methyl ethyl ketone, methyl isobutylketone and cyclohexanone; esters such as ethyl acetate, propyl acetateand butyl acetate; nitriles such as acetonitrile, propionitrile,butyronitrile and isobutyronitrile; carboxylic acids such as acetic acidand propionic acid; alcohols such as methanol, ethanol, 1-propanol,2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol and2-methyl-2-propanol; amides such as formamide, N,N-dimethylformamide,N,N-dimethylacetamide, N-methyl-2-pyrrolidone andhexamethylphosphoroamide; sulfoxides such as dimethyl sulfoxide;sulfones such as sulforane; water; and mixtures thereof.

In the reactions of each of the steps of Process A through Process G,the reaction temperature differs depending on solvent, startingmaterial, reagent and the like, and is selected appropriately. Inaddition, the reaction time differs depending on solvent, startingmaterial, reagent and the like, and is selected appropriately.

In the reactions of each of the steps of Process A through Process G,the desired compound of each of the steps can be isolated from areaction mixture in accordance with ordinary methods after completion ofthe reaction. The desired compound may be obtained by, for example, (i)removing insoluble matters such as catalyst as necessary, (ii)extracting the desired compound by adding water and solvent which isimmiscible with water (for example, ethyl acetate and the like) to thereaction mixture, (iii) washing the organic layer with water and dryingit as necessary by using a drying agent such as anhydrous magnesiumsulfate, and (iv) distilling off the solvent. The obtained desiredcompound can be further purified as necessary, by ordinary methods (forexample, recrystallization, reprecipitation, or silicagel columnchromatography). In addition, the desired compound of each procedure canalso be used in the subsequent reaction without purification.

(Process A)

Process A shows a method of manufacturing a compound represented by theformula (I) [which may include a compound represented by the formula(II)] or a pharmacologically acceptable salt thereof.

(Step A-1)

Step A-1 is a procedure to allow publicly known compound (1) to reactwith an alcohol represented by the formula R³OH in the presence of acid,to produce compound (2). The alcohol represented by the formula R³OH areeither publicly known, or can easily be produced from a publicly knowncompound, and is preferably methanol.

The acid used is not limited so long as it is used for esterification ofa carboxyl group using an alcohol, and may be for example, an organicacid such as acetic acid, propionic acid, trifluoroacetic acid andpentafluoropropionic acid, an organic sulfonic acid such asp-toluenesulfonic acid, camphorsulfonic acid andtrifluoromethanesulfonic acid, or an inorganic acid such as hydrogenchloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuricacid and nitric acid, preferably an inorganic acid, and most preferablysulfuric acid.

In Step A-1, a compound represented by the formula HC(OR³)₃ may be usedto accelerate the reaction. The compound represented by the formulaHC(OR³)₃ is either publicly known, or can easily be produced from apublicly known compound. The compound represented by the formulaHC(OR³)₃ is preferably trimethyl orthoformate [HC(OMe)₃]. R³ in thecompound represented by the formula HC(OR³)₃ is preferably the same asR³ in the alcohol represented by the formula R³OH.

The solvent used is preferably an aromatic hydrocarbon, a halogenatedhydrocarbon, an ether or an alcohol represented by the formula R³OH,more preferably an alcohol represented by the formula R³OH, and mostpreferably methanol.

The reaction temperature is preferably −20° C. to 100° C., and morepreferably 20° C. to 60° C.

The reaction time is preferably 30 minutes to 40 hours, and morepreferably 1 to 10 hours.

(Step A-2)

Step A-2 is a procedure to allow compound (2) to react with acetic acidanhydride in the presence of acid, to produce compound (3).

The acid used is not limited so long as it promotes formation of acarbon-carbon double bond by acetic acid elimination at the 2- and3-positions of the tetrahydropyrane ring, formation of an oxazoline ringat the 4- and 5-positions of the tetrahydropyrane ring, and acetylationof the hydroxyl group at the 1-, 2-, and 3-positions of the side chain.For example, it may be an organic acid such as acetic acid, propionicacid, trifluoroacetic acid and pentafluoropropionic acid, an organicsulfonic acid such as p-toluenesulfonic acid, camphorsulfonic acid andtrifluoromethanesulfonic acid, or an inorganic acid such as hydrogenchloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuricacid and nitric acid, preferably an inorganic acid, and most preferablysulfuric acid.

The solvent used is preferably a hydrocarbon, and most preferably1-heptane. It is also preferable that Step A-2 is conducted in theabsence of solvent.

The reaction temperature is preferably −20° C. to 100° C., and morepreferably 0° C. to 60° C.

The reaction time is preferably 30 minutes to 60 hours, and morepreferably 1 to 20 hours.

(Step A-3)

Step A-3 is a procedure to allow compound (3) to react with a compoundrepresented by the formula NaOR³, to produce compound (4).

In Step A-3, the compound represented by the formula NaOR³ is preferablysodium methoxide or sodium ethoxide, and most preferably sodiummethoxide. In Step A-3, a compound represented by the formula LiOR³ orKOR³ may be used instead of the compound represented by the formulaNaOR³. R³ in the compound represented by the formula NaOR³, LiOR³ orKOR³ is preferably the same as R³ of compound (3).

The solvent used is preferably an alcohol, more preferably methanol orethanol, and most preferably methanol. The solvent used is preferably analcohol represented by the formula R³OH [wherein R³ is the same as R³ ofthe compound represented by the formula NaOR³].

The reaction temperature is preferably −20° C. to 70° C., and morepreferably 0° C. to 50° C.

The reaction time is preferably 1 minute to 5 hours, and more preferably5 minutes to 1 hour.

(Step A-4)

Step A-4 is a procedure to allow compound (4) to react with compound (5)or compound (6), to produce compound (7). Compound (5) or compound (6)is either publicly known, or can easily be produced from a publiclyknown compound.

In Step A-4, of compound (5) and compound (6), compound (5) ispreferably used, more preferably dimethyl carbonate [(MeO)₂CO] ordiethyl carbonate, and most preferably dimethyl carbonate.

In Step A-4, in the case where compound [(R⁶O)₂CO], in which R⁴ and R⁵of compound (5) together form an oxo group, is used, a base may befurther used, preferably. Such base is not limited so long as it is usedfor conversion of 1,2-diol into cyclic carbonate, and may be forexample, an alkali metal carbonate such as lithium carbonate, sodiumcarbonate, potassium carbonate and cesium carbonate; an alkali metalhydrogencarbonate such as lithium hydrogencarbonate, sodiumhydrogencarbonate and potassium hydrogencarbonate; an alkali metalhydroxide such as lithium hydroxide, sodium hydroxide and potassiumhydroxide; an alkaline earth metal hydroxide such as calcium hydroxideand barium hydroxide; an alkali metal hydride such as lithium hydride,sodium hydride and potassium hydride; an alkali metal amide such aslithium amide, sodium amide and potassium amide; an alkali metalalkoxide such as lithium methoxide, sodium methoxide, sodium ethoxide,sodium tert-butoxide and potassium tert-butoxide; a lithium alkyl amidesuch as lithium diisopropylamide; a lithium silyl amide such as lithiumbistrimethylsilyl amide and sodium bistrimethylsilyl amide; or anorganic amine such as triethylamine, tributylamine,N,N-diisopropylethylamine, N-methylpiperidine, N-methylmorpholine,N-ethylmorpholine, pyridine, picoline, 4-dimethylaminopyridine,4-pyrrolidinopyridine, 2,6-di(tert-butyl)-4-methylpyridine, quinoline,N,N-dimethylaniline, N,N-diethylaniline,1,5-diazabicyclo[4,3,0]non-5-ene (DBN), 1,4-diazabicyclo[2,2,2]octane(DABCO), 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU); preferably an alkalimetal carbonate, an alkali metal alkoxide or an alkali metal hydride,more preferably an alkali metal alkoxide, and most preferably sodiummethoxide.

In Step A-4, in the case where compound (5) [except for a compoundrepresented by the formula (R⁶O)₂CO] or compound (6) is used, an acidmay be further used, preferably. Such acid is not limited so long as itis used for conversion of 1,2-diol into cyclic acetal or cyclic ketal,and may be for example, an organic acid such as acetic acid, propionicacid, trifluoroacetic acid and pentafluoropropionic acid, an organicsulfonic acid such as p-toluenesulfonic acid, camphorsulfonic acid andtrifluoromethanesulfonic acid, or an inorganic acid such as hydrogenchloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuricacid and nitric acid.

In Step A-4, in the case where compound [ (R⁶O)₂CO], in which R⁴ and R⁵of compound (5) together form an oxo group, is used, the solvent used ispreferably an alcohol, more preferably methanol or ethanol, and mostpreferably methanol. In the case where compound (5) is used, the solventused is preferably an alcohol represented by the formula R⁶OH [whereinR⁶ is the same as R⁶ of compound (5)]. In addition, the solvent used ispreferably an alcohol represented by the formula R⁶OH [wherein R⁶ is thesame as R⁶ of compound (5)].

In Step A-4, in the case where compound (5) [except for a compoundrepresented by the formula (R⁶O)₂CO] or compound (6) is used, thesolvent used is preferably a halogenated hydrocarbon, an amide, or aketone, more preferably a ketone, and most preferably acetone. In a casewhere compound (5) [except for a compound represented by the formula(R⁶O)₂CO] is used and the solvent used is a ketone, the solvent ispreferably a ketone represented by the formula (6).

The reaction temperature is preferably −30° C. to −80° C., and morepreferably 0° C. to 50° C.

The reaction time is preferably 30 minutes to 60 hours, and morepreferably 1 to 20 hours.

(Step A-5)

Step A-5 is a procedure to allow compound (7) to react with a compoundrepresented by the formula (R²O)₂SO₂ in the presence of a base, toproduce compound (8). The compound represented by the formula (R²O)₂SO₂is either publicly known, or can easily be produced from a publiclyknown compound.

In Step A-5, the compound represented by the formula (R²O)₂SO₂ ispreferably dimethyl sulfuric acid [(MeO)₂SO₂].

The base used is not limited so long as it is used for alkylation of ahydroxyl group, and may be, for example, a base indicated in Step A-4,preferably an alkali metal hydride, and most preferably sodium hydride.

The solvent used is preferably an ether, an amide, or a mixture thereof,more preferably tetrahydrofuran, N,N-dimethylacetamide, or a mixturethereof, and most preferably a mixture of tetrahydrofuran andN,N-dimethylacetamide.

The reaction temperature is preferably −50° C. to 80° C., and morepreferably −20° C. to 50° C.

The reaction time is preferably 10 minutes to 20 hours, and morepreferably 30 minutes to 10 hours.

(Step A-6)

Step A-6 is a procedure to allow compound (8) to react withtrimethylsilyl azide in the presence of a Lewis acid, to producecompound (9).

The Lewis acid used is not limited so long as it promotes azidationwhich is accompanied by ring opening of an oxazolidine ring, and may befor example, a zinc halide such as zinc chloride and zinc bromide; aboron trihalide such as boron trifluoride, boron trichloride and borontribromide, and their complexes with ethers or thioethers; a titanium(IV) alkoxide such as titanium (IV) methoxide, titanium (IV) ethoxide,titanium (IV) propoxide, titanium (IV) isopropoxide, titanium (IV)butoxide and titanium (IV) 2-ethylhexoxide; a zirconium (IV) alkoxidesuch as zirconium (IV) ethoxide, zirconium (IV) propoxide, zirconium(IV) isopropoxide isopropanol complex, zirconium (IV) butoxide andzirconium (IV) tert-butoxide; a scandium (III) alkoxide such as scandium(III) isopropoxide; a scandium salt such as scandiumtrifluoromethanesulfonate; a yttrium (III) alkoxide such as yttrium(III) isopropoxide; a yttrium salt such as yttriumtrifluoromethanesulfonate; a lanthanoid isopropoxide such as gadolinium(III) isopropoxide, dysprosium (III) isopropoxide, ytterbium (III)isopropoxide and erbium (III) isopropoxide; an aluminum alkoxide such asaluminum ethoxide, aluminum butoxide, aluminum sec-butoxide and aluminumtert-butoxide; preferably a titanium (IV) alkoxide, and most preferablytitanium (IV) isopropoxide.

The solvent used is preferably an aromatic hydrocarbon, an alcohol, or amixture thereof, more preferably 2-propanol, 2-methyl-2-propanol,toluene or a mixture thereof, and most preferably a mixture of2-methyl-2-propanol and toluene.

The reaction temperature is preferably −20° C. to 60° C., and morepreferably 0° C. to 30° C.

The reaction time is preferably 1 to 100 hours, and more preferably 5 to30 hours.

(Step A-7)

Step A-7 comprises (Step A-7a), a procedure to treat compound (9) withtriphenylphosphine; and (Step A-7b), a procedure to treat the compoundobtained in Step A-7a with a base and water.

(Step A-7a)

The solvent used is preferably an ether or an ester, more preferablytetrahydrofuran or ethyl acetate, and most preferably tetrahydrofuran.

The reaction temperature is preferably −30° C. to 100° C., and morepreferably 0° C. to 70° C.

The reaction time is preferably 1 minute to 20 hours, and morepreferably 5 minutes to 5 hours.

(Step A-7b)

The base used is not limited so long as it promotes hydrolysis of anester group and elimination of a cyclic carbonate group, and may be forexample, an alkali metal carbonate such as lithium carbonate, sodiumcarbonate, potassium carbonate and cesium carbonate; an alkali metalhydrogencarbonate such as lithium hydrogencarbonate, sodiumhydrogencarbonate and potassium hydrogencarbonate; an alkali metalhydroxide such as lithium hydroxide, sodium hydroxide and potassiumhydroxide; or an alkaline earth metal hydroxide such as calciumhydroxide and barium hydroxide, preferably an alkali metal hydroxide,more preferably sodium hydroxide or potassium hydroxide, and mostpreferably sodium hydroxide.

The solvent used is preferably an ether or an alcohol, more preferablytetrahydrofuran, methanol or ethanol, and most preferablytetrahydrofuran.

The reaction temperature is preferably −30° C. to 100° C., and morepreferably 0° C. to 70° C.

The reaction time is preferably 10 minutes to 20 hours, and morepreferably 30 minutes to 10 hours.

In the case where a protective group of 1,2-diol of compound (9) is acyclic acetal or cyclic ketal, deprotection of the 1,2-diol protectivegroup is conducted by treating the compound obtained in Step A-7a with abase and water, and then adjusting the pH of the reaction mixture toacidic.

(Step A-8)

Step A-8 is a procedure to allow compound (10) to react with compound(11), to produce compound (12). Compound (11) can be produced inaccordance with Process F.

The solvent used is preferably water, an amide, a ketone, a nitrile, analcohol or a mixture thereof, more preferably a mixture of water and analcohol, and most preferably a mixture of water and methanol.

The reaction temperature is preferably −30° C. to 80° C., and morepreferably 0° C. to 50° C.

The reaction time is preferably 1 to 160 hours, and more preferably 5 to80 hours.

(Step A-9)

Step A-9 is a procedure to allow compound (12) to react with water toproduce compound (13).

The solvent used is preferably an alcohol, water, or a mixture thereof,more preferably methanol, water, or a mixture thereof, and mostpreferably water.

The reaction temperature is preferably 0° C. to 160° C., and morepreferably 50° C. to 110° C.

The reaction time is preferably 30 minutes to 20 hours, and morepreferably 1 to 10 hours.

In Step A-8 and Step A-9, compound (13) can be produced also by reactingcompound (10) with a compound represented by the formula (23):

or a salt thereof. Compound (23) or a salt thereof is either publiclyknown, or can easily be produced from a publicly known compound.

In the present step, compound (23) or a salt thereof is preferably thehydrochloride of compound (23). In this step, a base (preferably anorganic amine or an alkali metal hydroxide, and more preferably analkali metal hydroxide) may be further used for the purpose ofcontrolling the pH during the reaction.

The solvent used is preferably an alcohol, water, or a mixture thereof,and most preferably a mixture of methanol and water.

The reaction temperature is preferably −20° C. to 70° C., and morepreferably 0° C. to 50° C.

The reaction time is preferably 1 to 200 hours, and more preferably 10to 100 hours.

The pH during the reaction is preferably 7 to 10, and more preferably 7to 9.

(Step A-10)

Step A-10 is a procedure to allow compound (13) to react with compound(14) in the presence of acid to produce compound (I) [which may containa compound represented by the formula (II)]. Compound (14) can beproduced in accordance with Process G.

In Step A-10, compound (14) is preferably trialkyl orthooctanoate[C₇H₁₅C(OR⁷)₃], and more preferably trimethyl orthooctanoate.

The acid used is not limited so long as it promotes acylation reactionof a hydroxyl group in which an ortho ester is used, and may be forexample, an organic acid such as acetic acid, propionic acid,trifluoroacetic acid and pentafluoropropionic acid, an organic sulfonicacid such as p-toluenesulfonic acid, camphorsulfonic acid andtrifluoromethanesulfonic acid, or an inorganic acid such as hydrogenchloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuricacid and nitric acid, preferably an organic sulfonic acid or aninorganic acid, more preferably p-toluenesulfonic acid, sulfuric acid orhydrogen chloride, and most preferably hydrogen chloride.

The solvent used is preferably an alcohol, and most preferably methanol.The solvent used is preferably an alcohol represented by the formulaR⁷OH [wherein R⁷ is the same as R⁷ of compound (14)].

The reaction temperature is preferably −30° C. to 80° C., and morepreferably 0° C. to 50° C.

The reaction time is preferably 5 minutes to 20 hours, and morepreferably 10 minutes to 5 hours.

In Step A-10, compound (I) [which may contain a compound represented bythe formula (II)] may be produced also by reacting compound (13) withcompound (15) and a compound represented by the formula R⁷—OH in thepresence of acid. Compound (15) can be produced in accordance withProcess G.

In this step, compound (15) is preferably a compound represented by theformula (15a):

The acid used is not limited so long as it promotes the presentreaction, and is preferably the aforementioned organic sulfonic acid orinorganic acid, more preferably p-toluenesulfonic acid, sulfuric acid,or hydrogen chloride, and most preferably hydrogen chloride.

The solvent used is preferably an alcohol, and most preferably methanol.The solvent used is preferably an alcohol represented by the formulaR⁷OH [wherein R⁷ is the same as R⁷ of compound (15)].

The reaction temperature is preferably −30° C. to 80° C., and morepreferably 0° C. to 50° C.

The reaction time is preferably 5 minutes to 20 hours, and morepreferably 10 minutes to 5 hours.

(Process B)

The production of compound (12) from compound (9) in Process A can alsobe conducted in accordance with Process B.

(Step B-1)

Step 8-1 is a procedure to reduce compound (9) by usingtriphenylphosphine and water, to produce compound (16).

The solvent used is preferably an ether or an ester, more preferablytetrahydrofuran or ethyl acetate, and most preferably ethyl acetate.

The reaction temperature is preferably 20° C. to 120° C., and morepreferably 50° C. to 90° C.

The reaction time is preferably 10 minutes to 20 hours, and morepreferably 30 minutes to 5 hours.

(Step B-2)

Step B-2 is a procedure to allow compound (16) to react with compound(11) to produce compound (17).

The solvent used is preferably an ether or an ester, more preferablytetrahydrofuran or ethyl acetate, and most preferably ethyl acetate.

The reaction temperature is preferably −30° C. to 80° C., and morepreferably 0° C. to 50° C.

The reaction time is preferably 1 to 80 hours, and more preferably 5 to40 hours.

(Step B-3)

Step B-3 is a procedure to treat compound (17) with a base to producecompound (12).

The base used is not limited so long as it promotes elimination of acyclic carbonate group and hydrolysis of an ester group, and may be forexample, an alkali metal carbonate, an alkali metal hydrogencarbonate,an alkali metal hydroxide, or an alkaline earth metal hydroxide asindicated in Step A-7b, preferably an alkali metal carbonate or analkali metal hydroxide, more preferably sodium carbonate or potassiumcarbonate, and most preferably potassium carbonate.

The solvent used is preferably an alcohol, and more preferably methanol.In the present step, it is preferable that water is present.

The reaction temperature is preferably −30° C. to 80° C., and morepreferably 0° C. to 50° C.

The reaction time is preferably 30 minutes to 20 hours, and morepreferably 1 to 10 hours.

In the case where the protective group of 1,2-diol is a cyclic acetal ora cyclic ketal, deprotection of the protective group of 1,2-diol isconducted by treating compound (17) with a base and then adjusting thepH of the reaction mixture to acidic.

(Process C)

The production of compound (12) from compound (8) in Process A can alsobe conducted in accordance with Process C.

(Step C-1)

Step C-1 is a procedure to allow compound (8) to react with a compoundrepresented by the formula NaOR³ to produce compound (18).

In Step C-1, the compound represented by the formula NaOR³ is preferablysodium methoxide.

Step C-1 can be conducted in a similar manner to Step A-3.

(Step C-2)

Step C-2 is a procedure to allow compound (18) to react with acetic acidanhydride in the presence of acid or base, to produce compound (19).

In Step C-2, in the case where an acid is used, it can be conducted in asimilar manner to Step A-2.

In Step C-2, in the case where a base is used, the base, used ispreferably an organic base as indicated in Step A-4, more preferablytriethylamine, tributylamine, N,N-diisopropylethylamine,4-dimethylaminopyridine, or a mixture thereof, and most preferably amixture of triethylamine and 4-dimethylaminopyridine.

The solvent used is preferably an aromatic hydrocarbon, an ester, or amixture thereof, more preferably an ester, and most preferably ethylacetate.

The reaction temperature is preferably −30° C. to 80° C., and morepreferably 0° C. to 50° C.

The reaction time is preferably 5 minutes to 10 hours, and morepreferably 10 minutes to 5 hours.

(Step C-3)

Step C-3 is a procedure to allow compound (19) to react withtrimethylsilyl aside in the presence of a Lewis acid, to producecompound (20).

Step C-3 can be conducted in a similar manner to Step A-6.

(Step C-4)

Step C-4 is a procedure to reduce compound (20) by usingtriphenylphosphine and water, to produce compound (21).

Step C-4 can be conducted in a similar manner to Step B-1.

(Step C-5)

Step C-5 is a procedure to allow compound (21) to react with compound(11) to produce compound (22).

Step C-5 can be conducted in a similar manner to Step B-2.

(Step C-6)

Step C-6 is a procedure to treat compound (22) with a base to producecompound (12).

Step C-6 can be conducted in a similar manner to Step B-3.

(Process D)

The production of compound (13) from compound (9) in Process A can alsobe conducted in accordance with Process D.

(Step D-1)

Step D-1 is a procedure to reduce compound (9) by usingtriphenylphosphine and water to produce compound (16).

Step D-1 can be conducted in a similar manner to Step B-1.

(Step D-2)

Step D-2 is a procedure to allow compound (16) to react with compound(23a) to produce compound (24).

In this procedure, a base (preferably an organic amine or an alkalimetal hydroxide, more preferably an alkali metal hydroxide) may befurther used for the purpose of controlling the pH during the reaction.

The solvent used is preferably an alcohol, water, or a mixture thereof,and most preferably a mixture of methanol and water.

The reaction temperature is preferably −20° C. to 70° C., and morepreferably 0° C. to 50° C.

The reaction time is preferably 1 to 200 hours, and more preferably 10to 100 hours.

The pH during the reaction is preferably 7 to 10, and more preferably 7to 9.

(Step D-3)

Step D-3 is a procedure to treat compound (24) with a base to producecompound (13).

Step D-3 can be conducted in a similar manner to Step B-3.

(Process E)

The production of compound (13) from compound (10) in Process A can alsobe conducted in accordance with Process E.

(Step E-1)

Step E-1 is a procedure to allow compound (10) to react with compound(23a) to produce compound (13).

Step E-1 can be conducted in a similar manner to Step D-2.

(Process F)

Process F shows a method of manufacturing compound (11).

(Step F-1)

Step F-1 is a procedure to allow compound (23a) to react with di-t-butyldicarbonate (Boc₂O) in the presence of a base to produce compound (25).Compound (23a) is either publicly known, or can easily be produced froma publicly known compound.

The base used is not limited so long as it is used for protection of anamino group by a tert-butoxycarbonyl group, and may be for example, analkali metal carbonate, an alkali metal hydrogencarbonate, an alkalimetal hydroxide, an alkaline earth metal hydroxide, an alkali metalhydride, or an organic amine as indicated in Step A-4, preferably anorganic amine, and most preferably N,N-diisopropylethylamine.

The solvent used is preferably an amide, and most preferablyN,N-dimethylformamide.

The reaction temperature is preferably −30° C. to 80° C., and morepreferably 0° C. to 50° C.

The reaction time is preferably 30 minutes to 20 hours, and morepreferably 1 to 5 hours.

(Step F-2)

Step F-2 is a procedure to allow compound (25) to react with a base togenerate an anion of compound (25), and then allow it to react withdi-t-butyl dicarbonate to produce compound (11).

The base used is not limited so long as it is used for protection of animino group by a tert-butoxycarbonyl group, and may be for example, analkali metal carbonate, an alkali metal hydrogencarbonate, an alkalimetal hydroxide, an alkaline earth metal hydroxide, an alkali metalhydride, an alkali metal amide, an alkali metal alkoxide, a lithiumalkyl amide, a lithium silyl amide, or an organic amine as indicated inStep A-4, preferably an alkali metal hydride, and most preferably sodiumhydride.

The solvent used is preferably an ether, and most preferablytetrahydrofuran.

The reaction temperature of the reaction of compound (25) with the baseis preferably −40° C. to 10° C., and more preferably −20° C. to 5° C.

The reaction time of the reaction of compound (25) with the base ispreferably 10 minutes to 5 hours, and more preferably 30 minutes to 2hours.

The reaction temperature of the reaction of the anion with di-tert-butyldicarbonate is preferably 20° C. to 120° C., and more preferably 50° C.to 90° C.

The reaction time of the reaction of the anion with di-tert-butyldicarbonate is preferably 30 minutes to 10 hours, and more preferably 1to 5 hours.

(Process G)

Process G shows a method of manufacturing compound (14) and compound(15).

(Step G-1)

Step G-1 is a procedure to allow compound (26) to react with a compoundrepresented by the formula R⁷OH in the presence of an acid representedby the formula HX, to produce compound (15). Compound (26) is eitherpublicly known, or can easily be produced from a publicly knowncompound.

In Step G-1, the acid represented by the formula HX is preferablyhydrogen chloride. In Step G-1, the compound represented by the formulaR⁷OH is preferably methanol.

The solvent used is preferably an ester, an aliphatic hydrocarbon, or anaromatic hydrocarbon, more preferably an ester, and most preferablymethyl acetate.

The reaction temperature is preferably −50° C. to 50° C., and morepreferably −20° C. to 20° C.

The reaction time is preferably 1 to 100 hours, and more preferably 5 to50 hours.

(Step G-2)

Step G-2 is a procedure to allow compound (15) to react with a compoundrepresented by the formula R⁷OH to produce compound (14).

In Step G-2, the compound represented by the formula R⁷OH is preferablymethanol. R⁷ in the compound represented by the formula R⁷OH ispreferably the same as R⁷ of compound (15). The volume ratio of thecompound represented by the formula R⁷OH with respect to compound (15)is preferably 0.5 to 5, and more preferably 1 to 3.

The solvent used is preferably a solvent which forms a bilayer system.Here, formation of a bilayer system means that the compound representedby the formula R⁷OH in the reaction solution and the solvent form twolayers that are not uniform and are separate from each other, and bystirring the reaction solution adequately, the compound present in thereaction solution, depending on its lipid solubility or watersolubility, can move to the other layer in which the compound can bedissolved more easily. The solvent used is preferably a carbohydrate,more preferably an aliphatic carbohydrate or an aromatic carbohydrate,even more preferably an aliphatic carbohydrate, further preferablycyclohexane, methylcyclohexane or ethylcyclohexane, particularlypreferably cyclohexane or methylcyclohexane, and most preferablymethylcyclohexane. The compound represented by the formula R⁷OH inexcess amount can also be used as the solvent.

The mixing ratio (volume ratio) of methylcyclohexane and methanol ispreferably 10:1 to 1:2, and more preferably 5:1 to 1:1.

The reaction temperature is preferably −20° C. to 90° C., and morepreferably 10° C. to 60° C.

The reaction time is preferably 30 minutes to 30 hours, and morepreferably 2 to 15 hours.

The neuraminic acid derivative (I) according to the present invention isknown to have excellent neuraminidase inhibitory activity and istherefore useful as a drug for treatment or prevention of influenza(refer to the aforementioned Patent Document 1 or 2).

In the case where the neuraminic acid derivative (I) according to thepresent invention is used as a medicament, especially as a drug fortreatment or prevention of influenza, it can be administered as such, orit can be mixed with a suitable excipient, diluent and the like that arepharmacologically acceptable, and administered as a tablet, capsule,granules, powders, syrup, injection, ointment, liquid formulation,suspension, aerosol, lozenge and the like. The medicament according tothe present invention can be administered orally or parenterally, and itis preferable that the compound (I), which is an active ingredient, isadministered in such manner that it can be directly delivered to thelungs or respiratory tract (which includes intraoral and intranasalportions).

These pharmaceutical drugs are produced through known methods by usingadditives such as excipients, binders, disintegrants, lubricants,stabilizers, corrigents for taste or smell, suspending agents, diluentsand solvents for formulation.

Although the dosage amount varies depending on symptoms, weight, age andthe like of the subject to be administered (a warm-blooded animal,preferably a human), it is preferable to administer it with a lowerlimit of 0.1 mg (preferably 1 mg) and an upper limit of 1000 mg(preferably 500 mg) per day, once a day or several times a day,depending on symptoms.

EXAMPLES

The present invention will be described in more detail with reference tothe following Examples; however, the scope of the present invention isnot limited to these.

Example 1 Synthesis of(4S,5R,6R)-5-acetamide-4-guanidino-6-[(1R,2R)-2-hydroxy-1-methoxy-2-(octanoyloxy)propyl]-5,6-dihydro-4H-pyran-2-carboxylicacid [compound (Ib)] Step A-1: Methyl N-acetylneuramate

Trimethyl orthoformate (116.67 g) and methanol (2720 ml) were added toN-acetyl neuraminic acid (340.00 g) and suspended. Concentrated sulfuricacid (8.63 g) was added to the suspension under stirring at roomtemperature, and the mixture was stirred for 3 hours at 40° C. Thesolvent was distilled off under reduced pressure until the amount ofsolution became approximately 1530 ml, dibutyl ether (4420 ml) was addedto the reaction solution at 30° C., and the reaction solution wasstirred at the same temperature for 1 hour. After it was further stirredfor 1 hour at 0° C., crystals were filtered. The crystals were washedwith a mixture of methanol (170 ml) and dibutyl ether (510 ml) and driedunder reduced pressure to give the title compound as a white solid(342.11 g, 96.3% yield).

MS (FAB): m/z 324 [M+H]⁺

HRMS (ESI): Exact mass calcd for C₁₂H₂₂NO₉ [M+H]⁺ 324. 2946. Found324.12966.

IR (KBr): 3340, 2938, 1741, 1638, 1553, 1438, 1375, 1279, 1127, 1033cm⁻¹

¹H NMR (D₂O, 500 MHz) 1.80 (1H, dd, J=12.1, 12.9 Hz), 1.94 (3H, s), 2.20(1H, dd, J=5.0, 12.9 Hz), 3.44 (1H, dd, J=1.0, 9.2 Hz), 3.51 (1H, dd,J=6.2, 11.8 Hz), 3.62 (1H, ddd, J=2.8, 6.2, 9.2 Hz), 3.73 (1H, dd,J=2.8, 11.8 Hz), 3.73 (3H, s), 3.81 (1H, dd, J=10.2, 10.2 Hz), 3.95 (1H,ddd, J=5.0, 10.2, 12.1 Hz), 3.96 (1H, dd, J=1.0, 10.2 Hz).

¹³C NMR (D₂O, 125 MHz): 22.2, 38.7, 52.1, 53.6, 63.2, 66.7, 68.3, 70.2,70.4, 95.4, 171.5, 174.9.

Step A-2: Methyl(3aS,4R,7aR)-4-[(1S,2R)-1,2,3-triacetoxypropyl]-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate

Heptane (600 ml) and anhydrous acetic acid (814.70 g) were added to thecompound obtained in Step A-1 (300.00 g) and suspended. The suspensionwas cooled to 0° C., and concentrated sulfuric acid (209.32 g) was addeddropwise under stirring at 40° C. or lower. After stirring the mixturefor 4 hours at 40° C., it was cooled to 0° C. and triethylamine (431.93g) was added dropwise at 40° C. or lower. The reaction solution wasadded dropwise to a mixture of water (1800 ml), 26% aqueous ammonia(916.79 g) and toluene (4500 ml) which was cooled to 0° C. understirring at 40° C. or lower. The reaction solution was stirred for 1hour at 25° C. After the reaction solution was allowed to stand, theorganic layer was separated and the solvent was distilled off underreduced pressure until the amount of solution became approximately 900ml to give a toluene solution of the title compound.

Step A-3: Methyl(3aS,4R,7aR)-4-[(1R,2R)-1,2,3-trihydroxypropyl]-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate

Methanol (1800 ml) and 25.4% methanol solution of sodium methoxide(15.79 g) were added to the toluene solution of the compound obtained inStep A-2 at room temperature, and the reaction solution was stirred for15 minutes at 25° C. The solvent of the reaction solution was distilledoff until the amount of solution became approximately 900 ml to give amethanol solution of the title compound.

Step A-4: Methyl(3aS,4R,7aR)-4-{(S)-hydroxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate

Dimethyl carbonate (961.26 g) was added to the methanol solution of thecompound obtained in Step A-3, and the mixture was stirred for 1 hour at25° C. and then further for 5 hours at 55° C. The reaction solution wascooled to 0° C., stirred for 5 minutes at the same temperature, andcrystals were filtered. The crystals were washed with methanol (600 ml)and dried under reduced pressure to give the title compound as a whitesolid (234.32 g, 80.6% yield).

MS (FAB): m/z 314 [M+H]⁺

Anal. calcd for C₁₃H₁₅NO₈: C, 49.84; H, 4.83; N, 4.47. Found C, 49.82;H, 4.58; N, 4.46.

IR (KBr): 3194, 1801, 1787, 1734, 1662, 1398, 1277, 1225, 1177, 1089,988 cm⁻¹ ¹H NMR (DMSO-d6, 500 MHz): 1.89 (3H, s), 3.24 (1H, dd, J=2.0,10.2 Hz), 3.72 (3H, s), 4.07 (1H, dd, J=2.0, 0.2.9 Hz), 4.15 (1H, dd,J=8.4, 10.2 Hz), 4.52 (1H, dd, J=7.2, 12.8 Hz), 4.54 (1H, dd, J=8.2,12.8 Hz), 4.90 (1H, dd, J=4.2, 8.4 Hz), 4.98 (1H, ddd, J=2.9, 7.2, 8.2Hz), 6.15 (1H, s), 6.27 (1H, d, J=4.2 Hz).

¹³C NMR (DMSO-d6, 125 MHz): 14.3, 53.0, 61.0, 65.9, 67.5, 72.3, 78.3,78.8, 108.1, 146.8, 155.3, 162.2, 166.3.

Step A-5: Methyl(3aS,4R,7aR)-4-{(S)-methoxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate

Tetrahydrofuran (80 ml) and N,N-dimethylacetamide (20 ml) were added tothe compound obtained in Step A-4 (20.00 g) and suspended. Thesuspension was stirred for 15 minutes at 0° C. After 60% sodium hydride(3.32 g) was added to the suspension and the mixture was stirred for 10minutes at 0° C., dimethyl sulfate (11.27 g) was added, followed bystirring for 2.25 hours at 15° C. Acetic acid (3.83 g) and toluene (200ml) were added to the reaction solution, the mixture was washed with 5%aqueous sodium hydrogencarbonate (100 ml), and the organic layer 1 andaqueous layer 1 were separated. The organic layer 1 was washed withwater (10 ml), and the organic layer 2 and aqueous layer 2 wereseparated. The aqueous layer 1 and aqueous layer 2 were combined,extracted with toluene (200 ml), and the organic layer 3 was separated.The organic layer 2 and organic layer 3 were combined and the solventwas distilled off under reduced pressure until the amount of solutionbecame approximately 60 ml to give a toluene solution of the titlecompound.

Step A-6: Methyl(4S,5R,6R)-5-acetamide-4-azide-6-{(S)-methoxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-5,6-dihydro-4H-pyran-2-carboxylate

2-Methyl-2-propanol (20 ml) and trimethylsilyl azide (14.71 g) wereadded to the compound obtained in Step A-5 at room temperature.Subsequently, titanium (IV) isopropoxide (5.44 g) was added at 10° C.,and the mixture was stirred for 20 hours at 20° C. (stereoisomer ratio15:1). After the reaction solution was cooled to 0° C., it was stirredfor 1 hour at the same temperature, and then crystals were filtered.After the crystals were washed with toluene (40 ml) and dried underreduced pressure to give the title compound as a pale yellowish whitesolid (20.73 g, 87.7% yield, stereoisomer ratio 66:1).

MS (FAB): m/z 371 [M+H]⁺

HRMS (ESI): Exact mass calcd for C₁₄H₁₉N₄O₈ [M+H]⁺ 371.12029. Found371.12018.

IR (KBr): 3314, 2106, 1795, 1731, 1668, 1550, 1379, 1285, 1180, 1075cm⁻¹

¹H NMR (DMSO-d6, 500 MHz): 1.89 (3H, s), 3.36 (3H, s), 3.71 (3H, s),3.88 (1H, dd, J=1.3, 2.0 Hz), 3.99 (1H, ddd, J=8.9, 9.2, 10.6 Hz), 4.20(1H, dd, J=1.3, 10.6 Hz), 4.29 (1H, dd, j=2.5, 9.2 Hz), 4.54 (1H, dd,J=7.9, 12.2 Hz), 4.56 (1H, dd, J=7.9, 12.2 Hz), 5.06 (1H, ddd, J=2.0,7.9, 7.9 Hz), 5.81 (1H, d, J=2.5 Hz), 8.16 (1H, d, J=8.9 Hz).

¹³C NMR (DMSO-d6, 125 MHz): 23.4, 47.0, 53.0, 59.0, 61.7, 66.1, 76.7,77.7, 79.1, 108.6, 144.7, 155.0, 161.7, 170.1.

The peak area ratios of the title compound and stereoisomer thereof weremeasured under the following HPLC measurement conditions.

HPLC Measurement Conditions (3)

Column: L-column ODS (4.6 mmID×250 mm, particle diameter 5 μm,manufactured by Chemicals Evaluation and Research Institute)Column temperature: 40° C.Measurement wavelength: 254 nmMobile phase: acetonitrile:0.02 mol/l aqueous ammonium acetatesolution=65:35Flow rate: 1 ml/minRetention time of the title compound: approximately 6.3 minutesRetention time of stereoisomer: approximately 6.6 minutes.

Step A-7:(4S,5R,6R)-5-Acetamide-4-amino-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylicacid

Triphenylphosphine (3.90 g) and tetrahydrofuran (20 ml) were added tothe compound obtained in Step A-6 (5.00 g) at room temperature, and themixture was stirred for 10 minutes at 50° C. To the reaction solutionwere added water (12.5 ml) and 25% aqueous sodium hydroxide (6.48 g) at50° C., followed by stirring for 2 hours at the same temperature. Thereaction solution was cooled to 0° C., concentrated hydrochloric aid(2.74 g) was added and the mixture was allowed to stand. Subsequently,the aqueous layer was separated to give an aqueous solution of the titlecompound.

Step A-8:(4S,5R,6R)-5-Acetamide-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylicacid

tert-Butyl(tert-butoxycarbonyliminopyrazol-1-yl-methyl)carbamate (4.19g) and methanol (40 ml) were added to the aqueous solution of thecompound obtained in Step A-7 at room temperature, and the mixture wasstirred for 43 hours at the same temperature. To the reaction solutionwas added water (12.5 ml) and the pH was adjusted to 8.35 byconcentrated hydrochloric acid. Subsequently, the solvent was distilledoff under reduced pressure until the amount of solution becameapproximately 25 ml. The obtained solution was washed with ethyl acetate(25 ml) 3 times, and the aqueous layer was separated. After the pH ofthe aqueous layer was adjusted to 2.75 with concentrated hydrochloricacid, it was extracted with ethyl acetate (45 ml) twice. The organiclayers were combined, and the solvent was distilled off under reducedpressure until the amount of solution became approximately 20 ml. Water(20 ml) was added to the concentrated solution, and the solvent wasdistilled off until the amount of solution became approximately 20 ml togive an aqueous solution of the title compound.

Step A-9:(4S,5R,6R)-5-Acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylicacid

The aqueous solution of the compound obtained in Step A-8 was stirredfor 3.7 hours at 80° C. After the reaction solution was cooled to 0° C.,methanol (50 ml) was added thereto, the mixture was stirred for 1.25hours at the same temperature, and crystals were filtered. The crystalswere washed with methanol (10 ml) and dried under reduced pressure togive the title compound as a white solid (3.34 g, 71.4% yield).

MS (FAB): m/z 347[M+H]⁺

Anal. calcd for C₁₃H₂₂N₄O₇: C, 45.08; H, 6.40; N, 16.18. Found C, 44.85;H, 6.16; N, 16.09.

IR (KBr): 3440, 3375, 3256, 1699, 1653, 1587, 1401, 1329, 1284, 1171,1087, 1029 cm⁻¹

¹H NMR (D₂O, 500 MHz): 1.94 (3H, s), 3.31 (3H, s), 3.45 (1H, dd, J=1.5,8.6 Hz), 3.57 (1H, dd, J=5.6, 12.0 Hz), 3.78 (1H, dd, J=3.0, 12.0 Hz),3.88 (1H, ddd, J=3.0, 5.6, 8.6 Hz), 4.10 (1H, dd, J=9.7, 9.7 Hz), 4.30(1H, dd, J=1.5, 9.7 Hz), 4.30 (1H, dd, J=2.2, 9.7 Hz), 5.52 (1H, d,J=2.2 Hz). ¹³C NMR (D₂O, 125 MHz): 22.1, 47.7, 51.8, 60.5, 62.5, 69.6,75.7, 77.8, 104.0, 149.4, 157.0, 169.0, 174.2.

Step A-10: (4S,5R,6R)-5-Acetamide-4guadino-6-[(1R,2R)-2-hydroxy-1-methoxy-2-(octanoyloxy)propyl]-5,6-dihydro-4H-pyran-2-carboxylicacid [compound (Ib)]

Methanol (15 ml) and trimethyl orthooctanoate (5.31 g) were added to thecompound obtained in Step A-9 (3.00 g) and suspended. To the suspensionwas added a 1 mol/l hydrogen chloride methanol solution (9.3 ml) at roomtemperature, followed by stirring for 1 hour at the same temperature.The solvent was distilled off under reduced pressure until the amount ofsolution became approximately 10.5 ml, and water (30 ml) was added tothe reaction solution and the mixture was washed with ethyl acetate (15ml) twice. The aqueous layer was separated, and pH was adjusted to 7with a 16.5% aqueous sodium carbonate solution. After stirring thereaction solution for 10 minutes at room temperature, pH was adjusted to8.8 with a 16.5% aqueous sodium carbonate solution, and then thereaction solution was stirred for 2 hours while maintaining the same pH.Subsequently, pH was adjusted to 5.7 with concentrated hydrochloric acidat room temperature, and the reaction solution was stirred for 1 hour at0° C. while maintaining the same pH. Crystals were filtered, washed withwater (12 ml), and dried under reduced pressure. The crystals wereallowed to absorb moisture at room temperature in the atmosphere for 5hours to give the crude title compound as white crystals (3.89 g, 95.1%yield). Methanol (12 ml) was added to the crude title compound (2.00 g)to dissolve it at 37° C. After methanol (2 ml) and water (28 ml) wereadded to the solution at the same temperature, the solution was stirredfor 1 hour at 25° C., and then crystals were filtered. The crystals werewashed with a mixture of methanol (2 ml) and water (4 ml), followed bydrying under reduced pressure. The crystals were allowed to absorbmoisture at room temperature in the atmosphere for 5 hours to give thetitle compound as a white crystal (1.84 g, 92.0% yield, chemical purity:99.72%, compound (Ib): compound (IIb)=97:3, content of compound (13)[R²=methyl group]: 0.02%, content of compound (VII) [R¹=1-heptyl group,R²=methyl group]: 0.08%, content of compound (VIII) [R¹=1-heptyl group]:0.04%).

MS (FAB): m/z 473[M+H]⁺

KF moisture value: 3.9%

Anal. calcd for C₂₁H₃₆N₄O₈. 1.065H₂O: C, 51.29; H, 7.82; N, 11.39. FoundC, 51.21; H, 7.82; N, 11.32.

IR (KBr): 3334, 3289, 2929, 1736, 1665, 1640, 1401, 1325, 1283, 1173,1114 cm⁻¹ ¹H NMR (CD₃OD, 500 MHz): 0.88 (3H, t, J=7.0 Hz), 1.25-1.34(8H, m), 1.62 (2H, tt, J=7.2, 7.5 Hz), 1.99 (3H, s), 2.35 (2H, t, J=7.5Hz), 3.38 (3H, s), 3.45 (1H, dd, J=2.5, 8.2 Hz), 4.09-4.14 (2H, m), 4.23(1H, dd, J=9.0, 9.0 Hz), 4.29-4.36 (3H, m), 5.55 (1H, d, J=2.5 Hz). ¹³CNMR (CD₃OD, 125 MHz): 13.1, 21.5, 22.3, 24.7, 28.8, 28.9, 31.5, 33.7,47.8, 51.4, 60.0, 65.5, 67.4, 76.1, 78.9, 102.3, 150.3, 157.6, 168.1,172.2, 174.1.

Example 2 Synthesis ofmethyl(3aS,4R,7aR)-4-((S)-hydroxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl)-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate(compound (7) [R⁴,R⁵=oxo group]) Step A-1: Methyl N-acetylneuramate

Trimethyl orthoformate (5.14 g) and methanol (120 ml) were added toN-acetyl neuraminic acid (1) (15.00 g) and suspended. Concentratedsulfuric acid (0.38 g) was added at room temperature under stirring, andthe reaction solution was stirred for 3 hours at 40° C. After thecompletion of the reaction, N,N-dimethylacetamide (15 ml) was added tothe reaction solution, and then the solvent was distilled off underreduced pressure until the amount of solution became approximately 40ml. Water (7.5 ml) and ethyl acetate (150 ml) were added to theconcentrated solution at 20° C., the mixture was stirred for 0.5 hoursat 30° C., and then ethyl acetate (150 ml) was added and stirred foranother 0.5 hours at the same temperature. After stirring for 2 hours at0° C., crystals were filtered, and the crystals were washed with ethylacetate (30 ml) which was cooled to 0° C. to give moist crystals of thetitle compound (15.65 g).

Step A-2: Methyl(3aS,4R,7aR)-4-[(1S,2R)-1,2,3-triacetoxypropyl]-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate

Anhydrous acetic acid (25.72 g) was added to the moist crystals obtainedin Step A-1 (10.08 g) and suspended, and then concentrated sulfuric acid(6.61 g) was slowly added dropwise under stirring while maintaining thetemperature at 40° C. or lower. After stirring the reaction solution for5 hours at 40° C., the reaction solution was cooled to 0° C., andtriethylamine (13.64 g) was added dropwise at 40° C. or lower. Thisreaction solution was added dropwise to a cooled solution mixture ofwater (50 ml), 28% aqueous ammonia (27.27 g), and toluene (140 ml) whilemaintaining the temperature at 40° C. or lower. The reaction solutionwas further stirred for 1 hour at 25° C. After the reaction solution wasallowed to stand, the separated organic layer was washed twice withwater (20 ml). The solvent was distilled off under reduced pressureuntil the amount of solution became approximately 30 ml to give atoluene solution of the title compound.

Step A-3: Methyl(3aS,4R,7aR)-4-[(1R,2R)-1,2,3-trihydroxypropyl]-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate

Methanol (60 ml) and a 28% sodium methoxide methanol solution (0.45 g)were added to the toluene solution of the compound obtained in Step A-2at room temperature, and the mixture was stirred for 15 minutes at 25°C. Subsequently, the reaction solution was concentrated under reducedpressure until the amount of solution became approximately 30 ml to givea methanol solution ofmethyl(3aS,4R,7aR)-4-[(1R,2R)-1,2,3-trihydroxypropyl]-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate(4).

Step A-4: Methyl(3aS,4R,7aR)-4-{(S)-hydroxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate

Dimethyl carbonate (30.35 g) was added to the methanol solution of thecompound obtained in Step A-3. The mixture was stirred for 1 hour at 25°C., and further stirred for 5 hours at 55° C. The reaction solution wascooled to 0° C., stirred for 5 minutes at the same temperature, and thencrystals were filtered. The crystals were washed with methanol (20 ml)and dried under reduced pressure to give the title compound as a whitesolid (7.06 g, 76.9% yield).

Example 3 Synthesis of(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylicacid (compound (13) [R²=methyl group]) Step B-1: Methyl(4S,5R,6R)-5-acetamide-4-amino-6-{(S)-methoxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-5,6-dihydro-4H-pyran-2-carboxylate

Ethyl acetate (40 ml), triphenylphosphine (7.79 g), and water (1.94 g)were added to the compound (10.00 g) obtained in Step A-6 of Example 1at room temperature, followed by stirring for 2.5 hours at 72° C. Thereaction solution was cooled to room temperature to give an ethylacetate solution of the title compound.

Step B-2: Methyl(4S,5R,6R)-5-acetamide-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-{(S)-methoxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-5,6-dihydro-4H-pyran-2-carboxylate

tert-Butyl(tert-butoxycarbonyliminopyrazol-1-yl-methyl)carbamate (8.80g) was added to the ethyl acetate solution of the compound obtained inStep B-1 at room temperature, and the mixture was stirred for 17.5 hoursat the same temperature. The solvent was distilled off under reducedpressure until the amount of solution became approximately 30 ml,toluene (100 ml) was added, and then insoluble matter was filtered. Thefiltrate was washed twice with water (30 ml), and the solvent of theseparated organic layer was distilled off under reduced pressure untilthe amount of solution became approximately 40 ml to give a toluenesolution of the title compound.

Step B-3:(4S,5R,6R)-5-Acetamide-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylicacid

Methanol (50 ml), water (23 ml), and potassium carbonate (11.20 g) wereadded to the toluene solution of the compound obtained in Step B-2 atroom temperature, and the mixture was stirred for 4 hours at the sametemperature. The reaction solution was cooled to 5° C., water (50 ml)was added, and then pH was adjusted to 8.3 by 7% hydrochloric acid. Thesolvent of the reaction solution was distilled off under reducedpressure until the amount of solution became approximately 110 ml,followed by washing with ethyl acetate (50 ml) 3 times, and the aqueouslayer was separated. The pH of the aqueous layer was adjusted to 2.7with 7% hydrochloric acid, followed by extracting with ethyl acetate (90ml) twice. The organic layers were combined, and the solvent wasdistilled off until the amount of solution became approximately 40 ml.Water (40 ml) was added to the concentrated solution, and the solventwas distilled off under reduced pressure until the amount of solutionbecame approximately 40 ml to give an aqueous solution of the titlecompound.

Step A-9:(4S,5R,6R)-5-Acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylicacid (compound (13) [R²=methyl group])

The aqueous solution of the compound obtained in Step B-3 was subjectedto a similar operation to Step A-9 of Example 1 to give the titlecompound as a white solid (6.71 g, 71.8% yield).

Example 4 Synthesis of(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylicacid (compound (13) [R²=methyl group]) Step C-1: Methyl(3aS,4R,7aR)-4-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate

Methanol (460 ml) and a 25.4% sodium methoxide methanol solution (14.36g) were added to a toluene solution (approximately 675 ml) of acompound, which was obtained by subjectingmethyl(3aS,4R,7aR)-4-{(S)-hydroxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate(46.00 g) to Step A-5 of Example 1, at room temperature, and the mixturewas stirred for 30 minutes at the same temperature. The solvent of thereaction solution was distilled off under reduced pressure until theamount of solution became approximately 138 ml, methanol (460 ml) wasadded, and the reaction solution was stirred for 30 minutes at roomtemperature. After acetic acid (4.41 g) was added to the reactionsolution and the solvent was distilled off under reduced pressure untilthe amount of solution became approximately 138 ml, toluene (230 ml) wasadded to the reaction solution and then the solvent was distilled offagain under reduced pressure until the amount of solution became 138 mlto give a toluene suspension of the title compound.

Step C-2: Methyl(3aS,4R,7aR)-4-[(1S,2R)-2,3-diacetoxy-1-methoxypropyl]-2-methyl-3a,7a-dihydro-4H-pyrano[3,4-d][1,3]oxazole-6-carboxylate

Ethyl acetate (184 ml) was added to the toluene suspension of thecompound obtained in Step C-1 and the mixture was stirred for 30 minutesat room temperature. Subsequently, triethylamine (66.69 g),N,N-dimethylaminopyridine (0.90 g), and anhydrous acetic acid (34.47 g)were added at 20° C. or lower, and the mixture was stirred for 1 hour atroom temperature. Toluene (460 ml) and 5% aqueous sodiumhydrogencarbonate (230 ml) were added to the reaction solution, followedby stirring for 1 hour at room temperature. After allowing the reactionsolution to stand, the organic layer was separated and washed with 5%aqueous sodium hydrogencarbonate (230 ml). The organic layer wasseparated, the solvent was distilled off under reduced pressure untilthe amount of solution became approximately 230 ml, and then insolublematter was filtered. The residue was washed with 138 ml of toluene, thefiltrate and the solution used for washing were combined, and thesolvent was distilled off under reduced pressure until the amount ofsolution became approximately 138 ml to give a toluene solution of thetitle compound.

Step C-3: Methyl(4S,5R,6R)-5-acetamide-4-azide-6-[(1S,2R)-2,3-diacetoxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylate

2-Methyl-2-propanol (47 ml) was added to the toluene solution of thecompound obtained in Step C-2. After cooling the mixture, titanium (IV)isopropoxide (8.68 g) and trimethylsilyl azide (23.92 g) were added,followed by stirring for 4 hours at 20° C. An aqueous sodium nitritesolution (sodium nitrite 14.32 g, water 329 ml) and hydrochloric acid(concentrated hydrochloric acid 23.77 g, water 74 ml) were added to thereaction solution at 10° C. or lower, and the reaction solution wasstirred for 30 minutes at room temperature. Subsequently, the solventwas distilled off under reduced pressure until the amount of solutionbecame approximately 494 ml. The concentrated solution was extractedwith ethyl acetate (471 ml), and organic layer 1 and aqueous layer 1were separated. Aqueous layer 1 was extracted with ethyl acetate (471ml), and organic layer 2 was separated. Organic layer 1 was washed twicewith 5% aqueous sodium hydrogencarbonate (235 ml), and organic layer 3was separated. Aqueous layer 2 and aqueous layer 3 were combined,extracted with organic layer 2, and organic layer 4 was separated.Organic layer 3 and organic layer 4 were combined, ethyl acetate (80 ml)was added, and the solvent was distilled off under reduced pressureuntil the amount of solution became approximately 245 ml to give anethyl acetate solution of the title compound.

Step C-4: Methyl(4S,5R,6R)-5-acetamide-4-amino-6-[(1S,2R)-2,3-diacetoxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylate

Triphenylphosphine (35.23 g) and water (8.80 g) were added to the ethylacetate solution of the compound obtained in Step C-3 at 0° C., and themixture was stirred for 2 hours at 72° C. The reaction solution wascooled to room temperature to give an ethyl acetate solution of thetitle compound.

Step C-5: Methyl(4S,5R,6R)-5-acetamide-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-[(1S,2R)-2,3-diacetoxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylate

tert-Butyl(tert-butoxycarbonyliminopyrazol-1-yl-methyl)carbamate (39.79g) was added to the ethyl acetate solution of the compound obtained inStep C-4 at room temperature, the mixture was stirred for 1 hour at thesame temperature, and was then allowed to stand for 17 hours. After thesolvent was distilled off under reduced pressure until the amount ofsolution became approximately 141 ml, toluene (471 ml) was added to thereaction solution, followed by washing with water (141 ml) and a 10%aqueous sodium chloride solution (141 ml). The solvent of separatedorganic layer was distilled off under reduced pressure until the amountof solution became approximately 188 ml to give a toluene solution ofthe title compound.

Step C-6:(4S,5R,6R)-5-Acetamide-4-[2,3-bis(tert-Butoxycarbonyl)guanidino]-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylicacid

Methanol (235 ml), water (108 ml), and potassium carbonate (50.63 g)were added to the toluene solution of the compound obtained in Step C-5,and the mixture solution was stirred for 4.5 hours at room temperature.Water (235 ml) was added at 30° C. or lower, and then the pH of themixture was adjusted to 8.3 with 7% hydrochloric acid. The solvent wasdistilled off under reduced pressure until the amount of solution becameapproximately 518 ml, the reaction solution was washed with ethylacetate (235 ml) 3 times, and the aqueous layer was separated. The pH ofthe aqueous layer was adjusted to 2.7 with 7% hydrochloric acid,followed by extracting with ethyl acetate (423 ml) twice. The organiclayers were combined, the solvent was distilled off under reducepressure until the amount of solution became approximately 282 ml, andthe insoluble matter was filtered. The residue was washed with ethylacetate (376 ml), the filtrate and the solution used for washing werecombined, and then the solvent was distilled off under reduced pressureuntil the amount of solution became approximately 188 ml. Water (188 ml)was added to the concentrated solution, the solvent was distilled offuntil the amount of solution became approximately 188 ml to give anaqueous solution of the title compound.

Step A-9:(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylicacid (compound (13) [R²=methyl group])

The aqueous solution of the compound obtained in Step C-6 was subjectedto a similar operation to Step A-9 of Example 1 to give the titlecompound as a white solid (30.97 g, 62.3% yield).

Example 5 Synthesis of(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylicacid (compound (13) [R²=methyl group]) Step D-1: Methyl(4S,5R,6R)-5-acetamide-4-amino-6-{(S)-methoxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-5,6-dihydro-4H-pyran-2-carboxylate

Ethyl acetate (4 ml), water (0.194 g), and triphenylphosphine (0.78 g)were added to the compound (1.00 g) obtained in Step A-6 of Example 1,and the mixture was stirred for 2 hours at 70° C. The reaction solutionwas cooled to room temperature, and then the solvent was distilled offunder reduced pressure to give the crude title compound.

Step D-2: Methyl(4S,5R,6R)-5-acetamide-4-guanidino-6-{(S)-methoxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-5,6-dihydro-4H-pyran-2-carboxylate

Water (4 ml), methanol (1 ml), and 1H-pyrazole-1-carboxamidinehydrochloride (0.52 g) were added to the crude compound obtained in StepD-1, and the mixture was stirred for 65 hours at room temperature togive a solution of the title compound.

Step D-3:(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylicacid (compound (13) [R²=methyl group])

Methanol (1 ml) and potassium carbonate (0.75 g) were added to thecompound obtained in Step D-2, and after the mixture was stirred forapproximately 23 hours at room temperature, the amount of the titlecompound generated was measured by HPLC (amount generated 0.59 g, yield63.3%).

HPLC Measurement Conditions (4)

Column: L-column ODS (4.6 mmID×250 mm, particle diameter 5 μm,manufactured by Chemicals Evaluation and Research Institute)Column temperature: 40° C.Measurement wavelength: 210 nmMobile phase: 0.01M potassium dihydrogen phosphate buffer (pH3)/methanol/PIC B-7 (Low UV, manufactured by WatersCorporation)(950/50/1)Flow rate: 1 ml/minRetention time of the title compound: approximately 4.1 minutes.

Example 6 Synthesis of(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2,3-dihydroxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylicacid (compound (13) [R²=methyl group])

Step E-1: To an aqueous solution of a compound obtained by subjectingmethyl(4S,5R,6R)-5-acetamide-4-azide-6-{(S)-methoxy[(4R)-2-oxo-1,3-dioxolan-4-yl]methyl}-5,6-dihydro-4H-pyran-2-carboxylate(1.00 g) to a similar operation to Step A-7, was added1H-pyrazole-1-carboxamidine hydrochloride (1.01 g) in two portions. Themixture was stirred for approximately 100 hours at room temperaturewhile maintaining the pH in the range of 7 to 9. The amount of the titlecompound generated was measured under the HPLC measurement conditions(4) (amount generated 0.53 g, yield 56.5%).

Example 7 Synthesis of(4S,5R,6R)-5-acetamide-4-guadino-6-[(1R,2R)-2-hydroxy-1-methoxy-2-(octanoyloxy)propyl]-5,6-dihydro-4H-pyran-2-carboxylicacid [compound (Ib)]

Methanol (20 ml) was added to methyl octaneimidoate hydrochloride (8.39g), and the mixture was stirred for 3 hours at 35° C. Subsequently, thecompound (5.00 g) obtained in Step A-9 of Example 1 and methanol (5 ml)were added at room temperature, and suspended. A 1.6 mol/l hydrogenchloride methanol solution (10.4 ml) was added to this suspension atroom temperature, followed by stirring for 2 hours at the sametemperature. The solvent was distilled off until the amount of solutionbecame approximately 20 ml, and water (60 ml) was added, followed bywashing twice with ethyl acetate (25 ml). The aqueous layer wasseparated, and the pH was adjusted to 7 with a 20% aqueous sodiumcarbonate solution, followed by stirring for 5 minutes at roomtemperature. Subsequently, the pH was adjusted to 8.7 with a 20% aqueoussodium carbonate solution, the reaction solution was stirred for 1.5hours, and then crystals were filtered. The crystals were washed withwater (10 ml), and then dried under reduced pressure to give the crudetitle compound as white crystal (6.21 g, 91.3% yield, chemical purity:99.51% compound (Ib):compound (IIb)=95:5, content of compound (13)[R²=methyl group]: <0.01%, content of compound (VII) [R¹=1-heptyl group,R²=methyl group]: 0.06%, content of compound (VIII) [R¹=1-heptyl group]:0.09%).

Example 8 Synthesis oftert-butyl(tert-butoxycarbonyliminopyrazol-1-yl-methyl)carbamate[compound (11)]

Step F-1: N,N-dimethylformamide (350 ml) and N,N-diisopropyl ethylamine(125 ml) were added to tert-butyl(iminopyrazol-1-yl-methyl)carbamate1H-pyrazole-1-carboxamidine hydrochloride (100 g), and then aN,N-dimethylformamide (50 ml) solution of ditert-butyl dicarbonate (152g) was added over 40 minutes at room temperature. After the mixture wasstirred for 2 hours at the same temperature, water (500 ml) was added,the mixture was extracted with toluene (500 ml), and organic layer 1 andaqueous layer 1 were separated. Organic layer 1 was further washed twicewith water (300 ml), and organic layer 2 was separated. Aqueous layer 1was extracted with toluene (500 ml), and organic layer 3 was separated.Organic layer 2 and organic layer 3 were combined, and the solvent wasdistilled off under reduced pressure until the amount of the solutionbecame approximately 300 ml. Hexane (500 ml) was added to the resultingsolution at room temperature, the mixture was stirred for 30 minutes,followed by stirring for 30 minutes under ice-cooling, and then crystalswere filtered. The crystals were washed with hexane (100 ml), and thendried under reduced pressure to give the title compound (120.3 g, 83.9%yield).

Step F-2:tert-Butyl(tert-butoxycarbonyliminopyrazol-1-yl-methyl)carbamate[compound (11)]

A tetrahydrofuran (100 ml) solution of the compound (50 g) obtained inStep B-1 was added to a tetrahydrofuran (100 ml) suspension of 60%sodium hydride (9.99 g) over 1 hour while maintaining the temperature inthe range of −5° C. to 0° C. After the mixture was stirred for 30minutes at the same temperature, a tetrahydrofuran (100 ml) solution ofditert-butyl dicarbonate (57.1 g) was added while maintaining thetemperature from −5° C. to 0° C., and then tetrahydrofuran (250 ml) wasadded. After the reaction solution was stirred for 2 hours under reflux,acetic acid (20.4 ml) was added at room temperature, and the solvent wasdistilled off under reduced pressure until the amount of solution becameapproximately 150 ml. A 5% aqueous sodium hydrogencarbonate solution(500 ml) was added to the resulting solution and the mixture wasextracted with ethyl acetate (500 ml). The organic layer was washed withwater (150 ml), and the solvent was distilled off until the amount ofsolution became approximately 75 ml. Hexane (200 ml) was added to theresidue at room temperature, and seed crystal was inoculated. Afterstirring the solution for 40 minutes under ice-cooling, crystals werefiltered, washed with hexane (50 ml), and dried under reduced pressureto give the title compound (54.47 g, 73.8% yield).

¹H NMR (CDCl₃, 500 MHz) 1.49 (9H, s), 1.55 (9H, s), 6.41 (1H, dd, J=1.5,2.7 Hz), 7.62 (1H, dd, J=0.7, 1.5 Hz), 8.30 (1H, dd, J=0.7, 2.7 Hz),8.93 (1H, bra).

¹³C NMR (CDCl₃, 125 MHz): 28.1, 28.2, 81.4, 83.4, 109.8, 129.0, 139.2,142.8, 149.4, 157.4.

Example 9 Synthesis of trimethyl orthooctanoate (compound (14)[R¹=1-heptyl group, R⁷=methyl group]) Step G-1: Methyl octanimidatehydrochloride

Methanol (2.81 g) and methyl acetate (30 ml) were added to octanenitrile(10.00 g), and the mixture was cooled to 0° C. Hydrogen chloride (7.50g) was added and the mixture was stirred for 25 hours at the sametemperature. Methylcyclohexane (60 ml) was added to the reactionsolution, and then the solvent was distilled off under reduced pressure.Methylcyclohexane (20 ml) was added to the residue, the mixture wasstirred for 1.5 hours at room temperature, and then crystals werefiltered. The crystals were washed with methylcyclohexane and driedunder reduced pressure to give the title compound as a white solid(14.45 g, 93.4% yield).

MS (FAB): m/z 158 [M+H]⁺

HRMS (ESI): Exact mass calcd for C₉H₂₀NO [M+H]⁺ 158.15449. Found158.15433.

IR (KBr): 3139, 3109, 2925, 2857, 1712, 1627, 1474, 1411, 1213, 1100cm⁻¹

¹H NMR (CDCl₃, 500 MHz): 0.82 (3H, t, J=7.0 Hz), 1.19-1.33 (8H, m), 1.67(2H, tt, J=7.5, 7.8 Hz), 2.70 (2H, t, J=7.8 Hz), 4.24 (3H, s), 11.52(1H, brs), 12.46 (1H, brs). ¹³C NMR (CDCl₃, 125 MHz): 14.1, 22.6, 25.7,28.7, 28.8, 31.5, 32.9, 60.7, 180.5.

Step G-2: Trimethyl orthooctanoate (compound (14) [R¹=1-heptyl group,R⁷=methyl group])

Methylcyclohexane (240 ml) and methanol (80 ml) were added to thecompound (40.00 g) obtained in Step G-1, and the mixture was stirred for6 hours at 35° C. The reaction solution was cooled to 10° C., andmethylcyclohexane (20 ml) was added, followed by washing with 5% aqueoussodium hydrogencarbonate (280 ml). The reaction solution was furtherwashed with 5% aqueous sodium hydrogencarbonate (120 ml), and theorganic layer was separated. The insoluble matter was filtered, and theresidue was washed with methylcyclohexane (20 ml). Then, the filtrateand the solution used for washing were combined, and the solvent wasdistilled off under reduced pressure. The residue was purified bydistillation under reduced pressure (1.5-1.8 torr, b.p. 85-90° C.) togive the title compound as a colorless transparent oil (35.37 g, 83.8%yield).

MS (ESI): m/z 227 [M+Na]⁺

HRMS (ESI): Exact mass calcd for C₁₁H₂₄O₃Na [M+Na]⁺ 227.16231. Found227.16138.

IR (neat): 2955, 2928, 2854, 1466, 1241, 1153, 1078, 1047, 977 cm⁻¹

¹H NMR (CDCl₃, 500 MHz): 0.86 (3H, t, J=6.8 Hz), 1.23-1.33 (8H, m),1.67-1.71 (2H, m), 3.21 (9H, s).

¹³C NMR (CDCl₃, 125 MHz): 14.1, 22.7, 22.8, 29.3, 29.5, 30.5, 31.9,49.4, 116.0.

Comparative Example 1 Synthesis ofmethyl(4S,5R,6R)-5-acetamide-4-tert-butyldimethylsilyloxy-2-methoxy-6-{(S)-methoxy[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-tetrahydro-4H-pyran-2-carboxylate[compound (VIb)]

60% Sodium hydride (0.16 g) was added to a N,N-dimethylformamide (10 ml)solution of compound (VIa) (1.00 g) described in Process Z at 0° C. Themixture was stirred for 5 minutes at the same temperature and dimethylsulfate (0.31 g) was added at 0° C., followed by further stirring for 2hours at room temperature (peak area ratio of the title compound: 41.6%,peak area ratio of N-methylated compound: 12.2%). A saturated aqueousammonium chloride solution (10 ml) and water (2 ml) were added to thereaction solution, and the mixture was extracted with ethyl acetate (20ml) 3 times. The organic layer was washed once with 5% aqueous sodiumhydrogencarbonate (10 ml) and with water (10 ml) twice. Subsequently,the solvent was distilled off under reduced pressure. Diisopropyl ether(2 ml) was added to the residue, the mixture was stirred for 10 minutesat room temperature, and the mixture was further stirred for 30 minutesat 0° C. After that crystals were filtered. The crystals were washedwith diisopropyl ether (2 ml), and dried under reduced pressure to givethe title compound as a white solid (0.28 g, 27.3% yield, peak arearatio of the title compound: 97.2%, peak area ratio of N-methylatedcompound: 0.3%).

The peak area ratios of the title compound and the N-methylated compoundwere measured in accordance with the following HPLC measurementconditions.

HPLC Measurement Conditions (4)

Column: L-column ODS (4.6 mmID×250 mm, particle diameter 5 μm,manufactured by Chemicals Evaluation and Research Institute)Column temperature: 40° C.Measurement wavelength: 195 nmMobile phase: acetonitrile:0.02 M aqueous potassium dihydrogen phosphatesolution=60:40Flow rate: 1 ml/minRetention time of the title compound: approximately 8.6 minutesRetention time of the N-methylated compound: approximately 15.4 minutes

Comparative Example 2 Synthesis ofmethyl(4S,5R,6R)-5-acetamide-4-azide-6-[(1S,2R)-2,3-diacetoxy-1-methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylate[compound (IVg)]

N,N-dimethylformamide (250 ml), DOWEX° 50W-X8 (10.0 g), and sodium azide(10.0 g) were added to compound (IVf) (10.0 g) described in Process W,Process Y, and Process Z and the mixture was stirred for 7 hours at 80°C. (stereoisomer ratio 7:1). The reaction solution was cooled to roomtemperature, and was filtered through an ion exchange resin. The resinwas washed with methanol (50 ml), the solvent used for washing wascombined with the filtrate, and the solvent was distilled off underreduced pressure. Dichloromethane (100 ml), saturated aqueous sodiumhydrogencarbonate (50 ml), and water (50 ml) were added to theconcentrated residue, and the organic layer was separated afterstirring. The organic layer was washed with 10% aqueous sodium chloride(100 ml) and the solvent was distilled off under reduced pressure togive the unpurified title compound (10.34 g, stereoisomer ratio 6:1).

The peak area ratios of the title compound and the stereoisomer weremeasured in accordance with the following HPLC measurement conditions.

HPLC Measurement Conditions (5)

Column: L-column ODS (4.6 mmID×250 mm, particle diameter 5 μm,manufactured by Chemicals Evaluation and Research Institute)Column temperature: 40° C.Measurement wavelength: 254 nmMobile phase: acetonitrile:water=60:40Flow rate: 1 ml/minRetention time of the title compound: approximately 6.2 minutesRetention time of stereoisomer: approximately 6.6 minutes

Comparative Example 3 Synthesis ofdiphenylmethyl(4S,5R,6R)-5-acetamide-4-[2,3-bis(tert-butoxycarbonyl)guanidino]-6-[(1R,2R)-2-hydroxy-1-methoxy-3-(octanoyloxy)propyl]-5,6-dihydro-4H-pyran-2-carboxylate[compound (IVk)]

Dichloromethane (20 ml) and triethylamine (0.10 g) were added tocompound (IVj) (0.50 g) of Process W at 0° C., octyl chloride (0.14 g)was added dropwise at the same temperature, and the mixture was stirredfor 3.5 hours. Ethyl acetate (50 ml) was added to the reaction solution,and the mixture was washed with saturated aqueous sodiumhydrogencarbonate (30 ml) and saturated aqueous sodium chloride (10 ml).The organic layer was separated, dried with anhydrous sodium sulfate,and the solvent was distilled off under reduced pressure to give theunpurified title compound (0.57 g, 97.0% yield, peak area ratio of thetitle compound: 63.2%, peak area ratio of diacylated compound: 5.6%).

The peak area ratios of the title compound and the diacylated compoundwere measured in accordance with the following HPLC measurementconditions.

HPLC Measurement Conditions (6)

Column: L-column ODE (4.6 mmID×250 mm, particle diameter 5 μm,manufactured by Chemicals Evaluation and Research Institute)Column temperature: 40° C.Measurement wavelength: 254 nmMobile phase: acetonitrile:0.02 mol/l aqueous ammonium acetate=90:10Flow rate: 1 ml/minRetention time of the title compound: approximately 6.8 minutesRetention time of the diacylated compound: approximately 24.6 minutes

Comparative Example 4 Synthesis of trimethyl orthooctanoate (compound(14) [R¹=1-heptyl group, R⁷=methyl group])

Methanol (330 ml) and petroleum ether (1 L) were added to the compound(160.44 g) obtained in accordance with Step G-1 of Example 9, and themixture was stirred for 18 hours under reflux. The reaction solution wascooled to 0° C., and was allowed to stand for 2 hours at the sametemperature. The insoluble matter was filtered, and the solvent wasdistilled off under reduced pressure. The residue was purified bydistillation under reduced pressure (2.2 torr, b.p. 93-96° C.) to givethe title compound as a colorless transparent oil (78.60 g, 44.7%yield).

Comparative Example 5(4S,5R,6R)-5-Acetamide-4-guadino-6-[(1R,2R)-2-hydroxy-1-methoxy-2-(octanoyloxy)propyl]-5,6-dihydro-4H-pyran-2-carboxylicacid [compound (Ib)]

Compound (Vd) of Process Z was converted into compound (IVj) by thediphenylmethyl esterification reaction of Process W [the third reactionin the conversion procedure of compound (IVi) into compound (IVj)], thenconverted into compound (Ia) by Process W, and then the title compoundwas synthesized from compound (Ia) in accordance with the processdescribed in the Example of Patent Document 2. The quality of thesynthesized title compound was as follows: Chemical purity: 91.88%,compound (Ib):compound (IIb)=85:15, content of compound (13) [R²=methylgroup]: 3.54%, content of compound (VII) [R¹=1-heptyl group, R²=methylgroup]: 0.51%, content of compound (VIII) [R¹=1-heptyl group]: 0.97%

Preparation Example 1 Liquid Formulation 1

A liquid formulation is prepared containing the compound of Example 110% (w/w), benzalkonium chloride 0.04% (w/w), phenethyl alcohol 0.40%(w/w), and purified water 89.56% (w/w).

Preparation Example 2 Liquid Formulation 2

A liquid formulation is prepared containing the compound of Example 110% (w/w), benzalkonium chloride 0.04% (w/w), polyethylene glycol 40010% (w/w), propylene glycol 30% (w/w), and purified water 49.96% (w/w).

Preparation Example 3 Powders

A powder formulation is prepared containing the compound of Example 140% (w/w) and lactose 60% (w/w)

Preparation Example 4 Aerosol

An aerosol is prepared containing the compound of Example 1 10% (w/w),lecithin 0.5% (w/w), Freon 11 34.5% (w/w) and Freon 12 55% (w/w).

INDUSTRIAL APPLICABILITY

The novel method for manufacturing neuraminic acid derivatives via novelsynthetic intermediates according to the present invention is superiorfrom an industrial perspective, compared with known manufacturingmethods. In addition, neuraminic acid derivatives with high purity canbe obtained in high yield by the present manufacturing method.

Since neuraminic acid derivative with high purity, which is obtained bythe present production method, has excellent neuraminidase inhibitoryactivity, it is useful as a drug for prevention or treatment ofinfluenza.

1. A method of manufacturing a compound represented by the formulaR¹C(OR⁷)₃, wherein R¹ represents a C₁-C₁₉ alkyl group and R⁷ representsa C₁-C₆ alkyl group, comprising: reacting a compound represented by thefollowing formula (15):

wherein R¹ represents a C₁-C₁₉ alkyl group, R⁷ represents a C₁-C₆ alkylgroup and X represents Cl, Br, I, HSO₄ or NO₃, with a compoundrepresented by the formula R⁷—OH, wherein R⁷ represents a C₁-C₆ alkylgroup, in a solvent which forms a bilayer system.
 2. The manufacturingmethod according to claim 1, wherein the solvent which forms the bilayersystem is cyclohexane or methylcyclohexane.
 3. The manufacturing methodaccording to claim 1, wherein R¹ is a 1-heptyl group, R⁷ is a methylgroup and X is Cl.
 4. The manufacturing method according to claim 3,wherein R¹ is a 1-heptyl group, R⁷ is a methyl group and X is Cl.